Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators

ABSTRACT

The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are tricyclic indeno-pyrrole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).

FIELD OF THE INVENTION

The present invention generally relates to a series of compounds, topharmaceutical compositions containing the compounds, and to use of thecompounds and compositions as therapeutic agents. More specifically,compounds of the present invention are tricyclic indeno-pyrrolecompounds. These compounds are serotonin receptor (5-HT) ligands and areuseful for treating diseases, disorders, and conditions whereinmodulation of the activity of serotonin receptors (5-HT) is desired(e.g. addiction, anxiety, depression and obesity).

BACKGROUND OF THE INVENTION

Serotonin has been implicated in a number of diseases, disorders, andconditions that originate in the central nervous system, includingdiseases, disorders, and conditions related to, for example, sleeping,eating, perceiving pain, controlling body temperature, controlling bloodpressure, depression, anxiety, addiction and schizophrenia. Serotoninalso plays an important role in peripheral systems, such as thegastrointestinal system, where it has been found to mediate a variety ofcontractile, secretory, and electrophysiologic effects.

Because of the broad distribution of serotonin within the body, there isa need for drugs that affect serotonergic systems. In particular,agonists, partial agonists, and antagonists of serotonergic systems areof interest for the treatment of a wide range of disorders, includinganxiety, depression, hypertension, migraine, obesity, compulsivedisorders, schizophrenia, autism, neurodegenerative disorders (e.g.,Alzheimer's disease, Parkinsonism, and Huntington's chorea), andchemotherapy-induced vomiting. The major classes of serotonin receptors(5-HT₁₋₇) contain one to seven separate receptors that have beenformally classified. See Glennon, et al., Neuroscience and BehavioralReviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46,157-203.

For example, the 5-HT₂ family of receptors contains 5-HT_(2a),5-HT_(2b), and 5-HT_(2c) subtypes, which have been grouped together onthe basis of primary structure, secondary messenger system, andoperational profile. All three 5-HT₂ subtypes are G-protein coupled,activate phospholipase C as a principal transduction mechanism, andcontain a seven-transmembrane domain structure. There are distinctdifferences in the distribution of the three 5-HT₂ subtypes in a mammal.The 5-HT_(2b) and 5-HT_(2a) receptors are widely distributed in theperipheral nervous system, with 5-HT_(2a) also found in the brain. The5-HT₂, receptor has been found only in the central nervous system, beinghighly expressed in many regions of the human brain. See G. Baxter, etal. Trends in Pharmacol. Sci. 1995, 16, 105-110.

Subtype 5-HT_(2a) has been associated with effects includingvasoconstriction, platelet aggregation, and bronchoconstriction, as wellas certain CNS effects, while subtype 5-HT_(2c) has been associated withdiseases that include depression, anxiety, obsessive compulsivedisorder, addiction, panic disorders, phobias, psychiatric syndromes,and obesity. Very little is known about the pharmocologic role of the5-HT_(2b) receptor. See F. Jenck, et al., Exp. Opin. Invest. Drugs,1998, 7, 1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40, 2762-2769;J. R. Martin, et al., The Journal of Pharmacology and ExperimentalTherapeutics, 1998, 286, 913-924; S. M. Bromidge, et al., 1. Med. Chem.,1998, 41,1598-1612; G. A. Kennett, Drugs, 1998, 1, 4, 456-470; and A.Dekeyne, et al., Neuropharmacology, 1999, 38, 415-423.

U.S. Pat. Nos. 4,622,405; 5,049,564 and 5,244,888 and WO 90/06927disclose various indeno-pyrrole derivatives.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the formula:

where

-   R₁ is selected from the group consisting of H, halogen, C₁₋₁₀alkyl,    C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, N(R₆)₂, SR₆,    CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂, NR₆SO₂R₇, aryl, heteroaryl,    C₁₋₁₀alkylaryl, and C₁₋₁₀alkylhetroaryl; and when m+n=1, R₁ may also    be OR₆ or OCOR₇;-   R₂, R₃ and R₄ are independently selected from the group consisting    of H, halogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, perhaloalkyl,    CN, OR₆, N(R₆)₂, SR₆, OCOR₇, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂,    NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀alkylhetroaryl    or R₂ and R₃ together with the ring to which they are attached form    a 5 to 7 membered carbocyclic or heterocyclic ring;-   R₅ is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₁₀    alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, OR₆, N(R₆)₂, SR₆, OCOR₇,    CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, NR₆SO₂R₇, aryl, heteroaryl,    C₁₋₁₀alkylaryl, and C₁₋₁₀alkylhetroaryl, or R₄ and R₅ together with    the ring to which they are attached form a 6 to 8 membered aryl or    heteroaryl ring;-   R₅a is H; or R₅ and R_(5a) taken together form a cyclopropane ring;-   R₆ is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₁₀    alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, C₁₋₁₀alkyl-O—C₁₋₁₀alkyl, aryl,    heteroaryl, C₁₋₁₀alkyl-O-aryl, C₁₋₁₀ alkyl-O-heteroaryl,    C₁₋₁₀alkylaryl, and C₁₋₁₀alkylhetroaryl; and-   R₇ is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀    alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, C₁₋₁₀alkyl-O—C₁₋₁₀alkyl, aryl,    heteroaryl, C₁₋₁₀alkyl-O-aryl, C₁₋₁₀alkyl-O-heteroaryl, C₁₋₁₀    alkylaryl, and C₁₋₁₀ alkylhetroaryl; provided that if R₁, R₂, R₅ and    R₅a are H, then R₃ and/or R₄ must be H and the pharmaceutically    acceptable salts thereof.

Included herein are the various stereoisomers of the compounds ofFormula (I).

Another embodiment of the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Still another embodiment of the present invention provides a method oftreating a disease, disorder and/or condition in a mammal (e.g., animalor human), wherein a 5-HT_(2c) receptor is implicated and modulation ofa 5-HT_(2c) function is desired. The method comprises administering atherapeutically effective amount of a compound of Formula (1), or apharmaceutically acceptable salt thereof, to the mammal.

Yet another embodiment of the present invention comprises a method ofmodulating 5-HT receptor function with an effective amount of compoundof Formula (1), or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention provides a method oftreating or preventing diseases, disorders, and/or conditions of thecentral nervous system. The method comprises administering atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, to the mammal.

Specific diseases, disorders and/or conditions for which compounds ofthe Formula (I) may have activity include cardiovascular disorders,obesity, depression, schizophrenia, anxiety, obsessive compulsivedisorder, addiction, panic disorders, sleep disorders, migraine, Type 11diabetes, epilepsy, phobias and psychiatric syndromes.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described:

As used herein, the term “alkyl” includes straight chained and branchedhydrocarbon groups containing the indicated number of carbon atoms,typically methyl, ethyl, and straight chain and branched propyl andbutyl groups. The term “alkyl” also encompasses cycloalkyl, i.e., acyclic C₃-C₈ hydrocarbon group, such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Reference to an individual group or moiety,such as “propyl,” embraces only the straight chain group or moiety. Abranched chain isomer, such as “isopropyl,” is specifically referred to.

The term “alkenyl” as used herein, alone or in combination, refers to asubstituted or unsubstituted straight-chain or substituted orunsubstituted branched-chain alkenyl radical containing from 2 to 10carbon atoms. Examples of such radicals include, but are not limited to,ethenyl, E- and Z-pentenyl, decenyl and the like.

The term “alkynyl” as used herein, alone or in combination, refers to asubstituted or unsubstituted straight or substituted or unsubstitutedbranched chain alkynyl radical containing from 2 to 10 carbon atoms.Examples of such radicals include, but are not limited to, ethynyl,propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term “alkyl” is as defined above.Examples of suitable alkyl ether radicals include, but are not limitedto, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and the like.

The term “halo” is defined herein to include fluoro, chloro, bromo, oriodo. Similarly, the term “halogen” is defined herein to includefluorine, chlorine, bromine, and iodine.

The term “amino”, alone or in combination, includes the group —NH₂ or—NR_(a)R_(b) wherein R_(a) and R_(b) are independently hydrogen, alkylor aryl.

The term “aryl,” alone or in combination, is defined herein as amonocyclic or bicyclic aromatic group (e.g., phenyl or naphthyl) thatcan be unsubstituted or substituted, for example, with one or more, andin particular one to three of the following substituents selected fromthe group consisting of H, halo, CN, NO₂, CF₃, N₃, C₁₋₆alkyl, OH,NR^(a)R^(b), OC₁₋₆ alkyl, OR^(a), C(═O)NR^(a)R^(b), C(═S)NR^(a)R^(b),tetrazoyl, triazoyl, amidinyl, guanidinyl, thioguanidinyl,cyanoguanadinyl, and aryl. Generally, “aryl” denotes a phenyl group, oran ortho-fused bicyclic carbocyclic group having nine to ten ring atomsin which at least one ring is aromatic (e.g. naphthyl ortetrahydronaphthyl). The term “aryl” also is abbreviated in the variouschemical structures as “Ar.”

The term “carbocyclic” includes any closed ring of carbon atoms,including alicyclic and aromatic structures.

The term “heteroaryl” is defined herein as a monocyclic, bicyclic, ortricyclic ring system containing one, two, or three aromatic rings andcontaining at least one nitrogen, oxygen, or sulfur atom in an aromaticring, and which can be unsubstituted or substituted, for example, withone or more, and in particular one to three, substituents, like halo,alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro,amino, alkylamino, acylamino, alkylthio, alkylsulfonyl, andalkylsulfonyl. Examples of heteroaryl groups include, but are notlimited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4H-carbazolyl,acridinyl, benzo[b]thienyl, benzothiazolyl, 1,3-carbolinyl, carbazolyl,chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl,imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl, phenanthridinyl,phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, andxanthenyl. In one embodiment the term “heteroaryl” denotes a monocyclicaromatic ring containing five or six ring atoms containing carbon and 1,2, 3, or 4 heteroatoms independently selected from the group consistingof non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O,C₁₋₄alkyl, phenyl or benzyl. In another embodiment heteroaryl denotes anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, or tetramethylene diradical thereto.

The term “Het” generally represents a heterocyclic group, saturated orpartially unsaturated, containing at least one heteroatom selected fromthe group consisting of oxygen, nitrogen, and sulfur, and optionallysubstituted with C₁₋₆alkyl or C(═O)OR^(b). Typically “Het” is amonocyclic, bicyclic, or tricyclic group containing one or moreheteroatoms selected from the group consisting of oxygen, nitrogen, andsulfur. A “Het” group also can contain an oxo group (═O) attached to thering. Nonlimiting examples of Het groups include 1,3-dihydrobenzofuran,1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, furanyl, imidazolyl, 2H-pyran,2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl, imidazolinyl,indolinyl, isochromanyl, isoindolinyl, morpholine, oxazolyl,piperazinyl, piperidine, piperidynyl, pyrazolidine, pyrimidinyl,pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, andthiomorpholine.

Preferably, R₁ is C₁₋₅ alkyl, halogen, CF₃, aryl, heteroaryl or H; R₂,R₃ and R₄ are independently C₁₋₅alkyl, —O—R₆, halogen, CF₃, aryl,heteroaryl or H; R₅ is C₁₋₅-alkyl, —OR₆ or C₂₋₆alkene; and R₆ isC₁₋₅alkyl or H.

Presently preferred compounds include:

-   5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   5-Hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   6-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   5-(4-Flourobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   5-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole;-   6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   6,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   4,5-Dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;-   4,6-Dichloro-5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    and-   6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.

Certain compounds of the invention may exist in different isomeric (e.g.enantiomers and distereoisomers) forms. The invention contemplates allsuch isomers both in pure form and in admixture, including racemicmixtures. Enol forms are also included.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, e.g., hemi-hydrate. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water, ethanol, and the like are equivalent to the unsolvatedforms for the purposes of the invention.

Certain compounds of the invention also form pharmaceutically acceptablesalts, e.g., acid addition salts. For example, the nitrogen atoms mayform salts with acids. Examples of suitable acids for salt formation arehydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonicand other mineral carboxylic acids well known to those in the art. Thesalts are prepared by contacting the free base form with a sufficientamount of the desired acid to produce a salt in the conventional manner.The free base forms may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous hydroxidepotassium carbonate, ammonia, and sodium bicarbonate. The free baseforms differ from their respective salt forms somewhat in certainphysical properties, such as solubility in polar solvents, but the acidsalts are equivalent to their respective free base forms for purposes ofthe invention. (See, for example S. M. Berge, et al., “PharmaceuticalSalts,” J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein byreference.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention or separately by reacting a free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptableexcipients. The phrase “therapeutically effective amount” of thecompound of the invention means a sufficient amount of the compound totreat disorders, at a reasonable benefit/risk ratio applicable to anymedical treatment. It will be understood, however, that the total dailyusage of the compounds and compositions of the present invention will bedecided by the attending physician within the scope of sound medicaljudgement. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.0001 to about 1000mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.001 to about 5 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions can be specially formulated for oraladministration in solid or liquid form, for parenteral injection or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a component of the present invention and aphysiologically tolerable diluent. The present invention includes one ormore compounds as described above formulated into compositions togetherwith one or more non-toxic physiologically tolerable or acceptablediluents, carriers, adjuvants or vehicles that are collectively referredto herein as diluents, for parenteral injection, for intranasaldelivery, for oral administration in solid or liquid form, for rectal ortopical administration, among others.

The compositions can also be delivered through a catheter for localdelivery at a target site, via an intracoronary stent (a tubular devicecomposed of a fine wire mesh), or via a biodegradable polymer. Thecompounds may also be complexed to ligands, such as antibodies, fortargeted delivery.

Compositions suitable for parenteral injection may comprisephysiologically acceptable, sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), vegetable oils (such asolive oil), injectable organic esters such as ethyl oleate, and suitablemixtures thereof.

These compositions can also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfumingagents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Bioloqy, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. Prodrugs of the present invention may be rapidlytransformed in vivo to the parent compound of the above formula, forexample, by hydrolysis in blood. A thorough discussion is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of theA.C.S. Symposium Series, and in Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press (1987), hereby incorporated by reference.

The compounds of the present invention may be prepared by the proceduresset forth in Schemes 1, 2 and 3. The general analytical conditions setforth after the Schemes were utilized in all examples.

General Analytical Conditions:

HPLC analysis and purification was performed using a Waters 2525 binarygradient pump, Waters 2767 sample manager, waters 2487 UV detector (220and 254 nM), and Waters Micromass ZQ electrospray mass spec detector.The Micromass ZQ was set for both positive and negative ionization (conevoltage=25 and 50, respectively). Analytical HPLC analysis was performedas follows:

-   Waters XTerra MS C18 50×4.6 mm 3.5 μm column-   Mobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and    Acetonitrile-   Acetonitrile: 10 to 75% at 3.5 minutes, 75 to 99% at 3.9 minutes,    99% hold to 4.2 minutes, 99 to 10% at 4.5 minutes, re-equilibrate.    Preparative HPLC was performed as follows:-   Waters XTerra Prep MS C18 50×19 mm 5 μm column-   Mobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and    Acetonitrile-   Acetonitrile: 10 to 99% at 8 minutes, 99% hold to 9 minutes, 99 to    10% at 9.5 minutes, re-equilibrate-   NMR analysis was performed using a Bruker BioSpin UltraShield NMR    (300 MHz)

EXAMPLES Example 15-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-Bromo-5-methoxy-1-indanone. (Scheme 1)

N-bromosuccinimide (12.1 g, 67.9 mmol) and 2,2′-azobisisobutyronitrile(0.1 g, 0.6 mmol) were added to a solution of 5-methoxy-1-indanone (10.0g, 61.7 mmol) in carbon tetrachloride (104 mL). The reaction mixture wasstirred for 3 hours at 85° C. and then allowed to cool to roomtemperature. The reaction mixture was filtered through Celite, which wasthen-washed with CH₂Cl₂ (100 mL). The filtrate was washed with brine (50mL), dried over MgSO₄, and concentrated to afford the subtitle compound,which was used without further purification. MS calculated forC₁₀HgBrO₂+H: 241, observed: 241.

Step B. 5-Methoxy-inden-1-one

DBU (9.2 mL, 61.7 mmol) was added to a solution of5-methoxy-3-bromo-1-indanone (14.8 g, 61.7 mmol) in THF (100 mL) at −10°C. dropwise over 10 minutes. The resulting solution was stirred at −10°C. for 20 minutes, quenched via addition of saturated aqueous NH₄Cl (100mL), and extracted with EtOAc (3×100 mL). The combined organic extractswere washed with brine (100 mL), dried over MgSO₄, and concentrated. Thecrude product was purified by column chromatography (SiO₂) using a 0-35%ethyl acetate-hexanes gradient to afford 5.4 g (55%—two steps) of thesubtitle compound. ¹H NMR (CDCl₃ 300 MHz) δ 7.42 (d, 1H), 7.38 (d, 1H),6.62 (s, 1H), 6.60 (d, 1H), 5.89 (d, 1H), 3.85 (s, 3H) ppm. MScalculated for C₁₀H₈O₂+H: 161, observed: 161.

Step C.2-Benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

N-(Methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (17.3 mL, 67.6mmol) and TFA (3.4 mL) were added to a solution of 5-methoxy-inden-1-one(5.4 g, 33.8 mmol) in CH₂Cl₂ (165 mL) at 0° C. The reaction was stirredfor 3 hours at room temperature and quenched with saturated aqueousNaHCO₃ (165 mL). The organic layer was separated, washed with brine (100mL), dried over MgSO₄, and concentrated to afford the subtitle compound,which was used without further purification. MS calculated forC₁₉H₁₉NO₂+H: 294, observed: 294.

Step D.2-Benzyl-5-methoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassiumtert-butoxide (5.7 g, 50.7) were added to a solution of2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture wasstirred for 1 hour at room temperature then filtered through celite. Thecelite was washed with ether (200 mL), and the filtrate wasconcentrated. The crude product was purified by column chromatography(SiO₂) using a 0-35% ethyl acetate-hexanes gradient to afford 8.1 g(82%—two steps) of the subtitle compound. MS calculated for C₂₀H₂₁NO+H:292, observed: 292.

Step E. 5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Ammonium formate (8.1 g) and palladium (10 wt. % on activated carbon,4.0 g) were added to a solution of2-benzyl-5-methoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(8.1 g, 27.8 mmol) in MeOH(140 mL). The reaction mixture was stirred for4 hours at 60° C. and then filtered through celite. The celite waswashed with MeOH (200 mL) and the filtrate was concentrated to afford5.6 g (quantitative yield) of the title compound. An aliquot of thecrude product was purified by reverse-phase liquid chromatography toafford the title compound. MS calculated for C₁₃H₁₇NO+H: 204, observed:204.

Example 2 5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

Hydrogen sodium carbonate (11.7 g, 139 mmol) and ethyl chloroformate(3.2 mL, 33.4 mmol) were added to a solution of5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (fromExample 1, Step E) (5.6 g, 27.8 mmol) in THF/H₂O (140 mL, 1/1, v/v), andstirred overnight at room temperature. The reaction mixture was quenchedby addition of an aqueous HCl solution (200 mL, 1.0 M) and the productwas extracted with EtOAc (3×100 mL). The combined organic extracts weredried over MgSO₄ and concentrated. The crude product was purified bycolumn chromatography (SiO₂) using a 0-35% ethyl acetate-hexanesgradient to afford 2.7 g (35%) of the subtitle compound. ¹H NMR (CDCl₃300 MHz) δ 7.07 (d, 1H), 6.78 (m, 2H), 4.09 (m, 2H), 3.79 (m, 5H), 3.63(m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 1.26(m, 6H) ppm. MS calculated for C₁₆H₂₁NO₃+H: 276, observed: 276.

Step B. 5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

N-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(12 mg, 0.045 mmol) was dissolved in concentrated HCl (2 mL) and stirredfor 20 hours at 120° C. The reaction solution was cooled to roomtemperature, diluted with H₂O (2 mL), and washed with EtOAc (5 mL). Theaqueous solution was concentrated on a speed vac to afford the titlecompound as the hydrochloride salt. MS calculated for C₁₂H₁₅NO+H: 190,observed: 190.

Example 35-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

N-chlorosuccinimide (0.22 g, 1.6 mmol) and acetic acid (8 mL) were addedto a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.45 g, 1.6mmol) in DCE (8 mL), and stirred for 3 hours at 60° C. The reactionmixture was cooled to room temperature, diluted with CH₂Cl₂ (50 mL), andwashed with H₂O (50 mL). The organic extract was dried over MgSO₄ andconcentrated. The crude product was purified by column chromatography(SiO₂) using a 0-35% ethyl acetate-hexanes gradient to afford 250 mg(51%) of the subtitle compound. MS calculated for C₁₆H₂₀ClNO₃+H: 310,observed: 310.

Step B.5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Barium hydroxide octahydrate (0.63 g, 2.0 mmol) was added to a solutionof N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (61 mg, 0.2 mmol) in MeOH (4 mL), andstirred for 24 hours at reflux. The reaction mixture was cooled to roomtemperature and neutralized to pH=7 with aqueous HCl (50 mL, 1 M). Theproduct was extracted with CH₂Cl₂, dried over MgSO₄, and concentrated.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. MS calculated for C₁₃H₁₆ClNO+H: 238,observed: 238.

Example 45-Hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

A solution ofN-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 3, Step A) (61 mg, 0.2 mmol) in concentrated HCl wasstirred overnight at 120° C. The reaction solution was cooled to roomtemperature and concentrated on a speed vac. The crude product waspurified by reverse-phase liquid chromatography to afford the titlecompound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.04 (s, 1H), 6.73 (s, 1H), 3.52(m, 1H), 3.22 (m, 2H), 2.83 (m, 3H), 2.41 (m, 1H), 1.18 (d, 3H) ppm. MScalculated for C₁₂H₁₄ClNO+H: 224, observed: 224.

Example 5 6-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

BBr₃ (3.7 mL, 1.0 M in CH₂Cl₂) was added to a solution ofN-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 3, Step A) (0.49 g, 1.6 mmol) in CH₂Cl₂ (32 mL), andstirred overnight at room temperature. The excess BBr₃ was quenched withthe dropwise addition of H₂O(10 mL), and washed with saturated aqueousNaHCO₃ (50 mL) and brine (50 mL). The organic extract was dried overMgSO₄ and concentrated to afford the subtitle compound, which was usedwithout further purification. MS calculated for C₁₅H₁₈ClNO₃+H: 296,observed: 296.

Step B.N-Ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole,O-trifluoromethanesulfonate

Pyridine (0.23 mL, 2.85 mmol) and trifluoromethanesulfonic anhydride(0.32 mL, 1.90 mmol) were added to a solution ofN-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.28 g, 0.95 mmol) in CH₂Cl₂ (10 mL), and stirred for 1.5 hours at roomtemperature. The reaction was diluted with CH₂Cl₂ (10 mL), washed withH₂O (10 mL), aqueous HCl (1.0 M, 10 mL), saturated aqueous NaHCO₃ (10mL), and brine (10 mL). The organic extract was dried over MgSO₄ andconcentrated to afford the subtitle compound, which was used withoutfurther purification. MS calculated for C₁₆H₁₇F₃ClNO₅S+H: 428, observed:428.

Step C.N-Ethylcarbamate-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

To a mixture ofN-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole,o-trifluoromethanesulfonate (60 mg, 0.14 mmol), palladium(II) acetate (6mg, 0.028 mmol) and 1,3-bis(diphenylphosphino) propane (12 mg, 0.035mmol) in MeOH (0.5 mL) and DMSO (0.5 mL) was added Et₃N (0.2 mL, 1.4mmol). The resulting mixture was stirred for 2 hours at 80° C. thencooled to room temperature. The reaction mixture was diluted with EtOAc(5 mL) and then washed with H₂O (2 mL). The organic extract was driedover MgSO₄ and concentrated to afford 15 mg (35% yield) of the subtitlecompound, which was used Without further purification. MS calculated forC₁₅H₁₈ClNO₂+H: 280, observed: 280.

Step D. 6-Chloro-8-methyl-1,2;3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 4 usingN-ethylcarbamate-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified byreverse-phase liquid chromatography to afford the title compound. MScalculated for C₁₂H₁₄ClN+H: 208, observed: 208.

Example 65-(4-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-(4-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

4-Fluorobenzyl bromide (23 μL, 0.19 mmol) and potassium carbonate (100mg, 0.78 mmol) were added to a solution ofN-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 5, Step A) (46 mg, 0.16 mmol) in acetonitrile (3 mL), andstirred overnight at 80° C. The reaction was cooled to room temperature,concentrated by rotary evaporation and taken up in H₂O (5 mL). Theproduct was extracted with EtOAc (3×10 mL). The combined organicextracts were dried over MgSO₄ and concentrated to afford the subtitlecompound, which was used without further purification. MS calculated forC₂₂H₂₃ClFNO₃+H: 404, observed: 404.

Step B.5-(4-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-Ethylcarbamate-5-(4-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.51 (m, 2H), 7.23(m, 3H), 7.09 (s, 1H), 5.18 (m, 2H), 3.63 (m, 1H), 3.27 (m, 2H), 2.7-3.0(m, 3H), 2.45 (m, 1H), 1.18 (d, 3H) ppm. MS calculated forC₁₉H₁₉ClFNO+H: 332, observed: 332.

Example 75-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

The subtitle compound was prepared by the method of Example 6, Step AutilizingN-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 5, Step A) and benzyl bromide. The crude product wasobtained without further purification. MS calculated for C₂₂H₂₄ClNO₃+H:386, observed: 386.

Step B.5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydro-indeno[1,2-c]pyrrole.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.28-7.60 (m, 5H),7.19 (s, 1H), 7.10 (s, 1H), 5.18 (m, 2H), 3.63 (m, 1H), 3.27 (m, 2H),2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.18 (d, 3H) ppm. MS calculated forC₁₉H₂₀ClNO+H: 314, observed: 314.

Example 85-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-(2-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

The subtitle compound was prepared by the method of Example 6, Step AutilizingN-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 5, Step A) and 2-fluorobenzyl bromide. The crude productwas obtained without further purification. MS calculated forC₂₂H₂₃ClFNO₃+H: 404, observed: 404.

Step B.5-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-(2-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.58 (m, 1H), 7.44(m, 1H), 7.25 (m, 2H), 7.19 (s, 1H), 7.09 (s, 1H), 5.20 (m, 2H), 3.63(m, 1H), 3.27 (m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.22 (d, 3H) ppm.MS calculated for C₁₉H₁₉ClFNO+H: 332, observed: 332.

Example 95-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

The subtitle compound was prepared by the method of Example 6, Step AutilizingN-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 5 Step A) and 3-fluorobenzyl bromide. The crude productwas obtained without further purification. MS calculated forC₂₂H₂₃ClFNO₃+H: 404, observed: 404.

Step B.5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-(3-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.38 (m, 1H), 7.23(m, 2H), 7.14 (m, 2H), 7.02 (s, 1H), 5.16 (m, 2H), 3.58 (m, 1H), 3.24(m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.14 (d, 3H) ppm. MS calculatedfor C₁₉H₁₉ClFNO+H: 332, observed: 332.

Example 10 1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole

Step A. 2,2a,7,7a-Tetrahydro-cyclobuta[a]inden-1-one. (Scheme 2)

To a suspension of indene (1.2 mL, 10.0 mmol) and activated zinc (1.6 g,25.0 mmol) in ether (100 mL) was added a solution of trichloroacetylchloride (3.4 mL, 30.0 mmol) in ether (40 mL). The resulting mixture wasstirred for 4 hours at reflux. The reaction was cooled to roomtemperature, filtered through celite, and the celite washed with ether(2×100 mL). The organic filtrate was washed with H₂O (100 mL), driedover MgSO₄, and concentrated. The organic residue was dissolved in MeOH(100 mL). To this solution was added slowly zinc (5.0 g) and NH₄Cl (4.0g). The reaction mixture was stirred overnight at reflux. The reactionmixture was cooled to room temperature, filtered through celite, thecelite washed with MeOH (200 mL), and concentrated. The crude productwas purified by column chromatography (SiO₂) using a 0-35% ethylacetate-hexanes gradient to afford 1.4 g (89%—two steps) of the subtitlecompound. ¹H NMR (CDCl₃ 300 MHz) δ 7.24 (m, 4H), 4.06 (m, 2H), 3.63 (m,1H), 3.29 (d, 1H), 3.10 (m, 1H), 2.88 (d, 1H) ppm.

Step B. 2,2a,7,7a-Tetrahydro-cyclobuta[a]inden-1-one oxime

Sodium acetate (1.45 g, 17.7 mmol) and hydroxylamine hydrochloride (0.68g, 9.75 mmol) were added to a solution of2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (1.4 g, 8.86 mmol) in MeOH(18 mL), and stirred overnight at room temperature. The reactionsolution was concentrated via rotary evaporation. The residue wasdissolved in CH₂Cl₂ (100 mL), washed with H₂O (50 mL), dried over MgSO₄,and concentrated to give the subtitle compound, which was used withoutfurther purification. MS calculated for C₁₁H₁₁NO+H: 174, observed: 174.

Step C. 3,3a,8,8a-Tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one

Thionyl chloride (1.9 mL, 26.4 mmol) was added to a solution of2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one oxime (1.5 g, 8.8 mmol) in1,4-dioxane (44 mL), and stirred overnight at room temperature. Thereaction was quenched with saturated aqueous NaHCO₃ (100 mL), andextracted with EtOAc (3×50 mL). The organic extracts were washed withbrine, dried over MgSO₄, and concentrated to give the subtitle compoundand its regioisomer, which were used without further purification. MScalculated for C₁₁H₁₁NO+H: 174, observed: 174.

Step D. 1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole

A solution of 3,3a,8,8a-tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one(1.5 g, 8.8 mmol) in THF (44 mL) was cannulated to a solution of LAH inTHF (26.4 mL, 1.0 M solution in THF). The resulting solution was stirredfor 4 hours at 70° C., then overnight at room temperature. The reactionwas quenched via the stepwise addition of H₂O (1 mL), aqueous NaOH (1mL, 2.0 M solution), and H₂O (3 mL). The resulting mixture was filteredthrough celite, the celite washed with warm MeOH (200 mL), and thefiltrate concentrated to give the subtitle compound and its regioisomer,which were used without further purification. MS calculated forC₁₁H₁₃N+H: 160, observed: 160.

Step E.N-tert-Butylcarbamate-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Di-tert-butyl dicarbonate (2.0 g, 9.4 mmol) and sodium hydrogencarbonate (4.0 g, 47 mmol) were added to a solution of1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (1.5 g, 9.4 mmol) in H₂O/THF(46 mL, 1/1, v/v), and stirred overnight at room temperature. Thereaction mixture was diluted with H₂O (50 mL), and extracted with EtOAc(3×100 mL). The combined organic extracts were dried over MgSO₄ andconcentrated. The crude products (mixture of regioisomers) were purifiedand separated by column chromatography (SiO₂) using a 0-35% ethylacetate-hexanes gradient to afford 110 mg (5% yield—5 steps) of thesubtitle compound. MS calculated for C₁₆H₂₁NO₂+H: 260, observed: 260.

Step F. 1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole

N-tert-Butylcarbamate-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (110mg, 0.42 mmol) was dissolved in a HCl solution (5 mL, 4.0 M solution in1,4-dioxane) and stirred for 2 hours at room temperature. The reactionwas concentrated by rotary evaporation. The crude product was purifiedby reverse-phase liquid chromatography to afford the title compound. ¹HNMR (d₆-DMSO 300 MHz) δ 7.16 (m, 4H), 3.71 (m, 1H), 3.25 (m, 1H),3.0-3.18 (m, 2H), 2.79-3.00 (m, 2H), 2.72 (m, 1H), 2.45 (m, 1H) ppm. MScalculated for C₁₁H₁₃N+H: 160, observed: 160.

Example 11 6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 6-Chloro-1H-indene. (Scheme 2)

Sodium borohydride (2.3 g, 60.2 mmol) was added to a solution of5-chloro-1-indanone (10.0 g, 60.2 mmol) in MeOH (300 mL), and stirredfor 3 hours at room temperature. The reaction was quenched with H₂O (100mL), and extracted with CH₂Cl₂ (3×100 mL). The combined extracts weredried over MgSO₄ and concentrated.

The organic residue was dissolved in toluene (300 mL) and treated withp-toluenesulfonic acid monohydrate (1.2 g, 6.02 mmol), which was stirredfor 1 hour at 90° C. The reaction was cooled to room temperature, washedwith brine (150 mL), dried over MgSO₄, and concentrated to give 6.9 g(76%—two steps) of the subtitle compound, which was used without furtherpurification.

Step B. 5-Chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one

The subtitle compound was prepared by the method of Example 10, Step Autilizing 6-chloro-1H-indene (3.4 g, 22.6 mmol). The crude product wasobtained without further purification.

Step C. 5-Chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one oxime

The subtitle compound was prepared by the method of Example 10, Step Butilizing 5-chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (2.0 g,10.4 mmol). The crude product was obtained without further purification.MS calculated for C₁₁H₁₀ClNO+H: 208, observed: 208.

Step D. 6-Chloro-3,3a,8,8a-tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one

The subtitle compound was prepared by the method of Example 10, Step Cutilizing 5-chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (2.0 g,10.4 mmol) The crude product was obtained without further purification.MS calculated for C₁₁H₁₀ClNO+H: 208, observed: 208.

Step E. 6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 10, Step Dutilizing6-chloro-3,3a,8,8a-tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one (2.0 g,10.4 mmol). The crude product was obtained without further purification.MS calculated for C₁₁H₁₂ClN+H: 194, observed: 194.

Step F.N-tert-Butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 10, Step Eutilizing 6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (2.0 g,10.4 mmol). The crude product was obtained without further purification.MS calculated for C₁₆H₂₀ClNO₂+H: 294, observed: 294.

Step G. 6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 10, Step FutilizingN-tert-butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.25 (m, 3H), 3.71(m, 1H), 3.19 (m, 2H), 3.05 (m, 2H), 2.88 (m, 1H), 2.77 (m, 1H), 2.45(m, 1H) ppm. MS calculated for C₁₁H₁₃ClN+H: 194, observed: 194.

Example 126-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-tert-Butylcarbamate-6-(2,6-difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 2)

Triphenylphosphine (2 mg), palladium(II) acetate (1 mg),2,6-difluorophenyl boronic acid (20 mg, 0.12 mmol), and aqueous sodiumcarbonate (0.15 mL, 0.3 mmol) were added to a solution of(N-tert-butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[112-c]pyrrole(from Example 11, Step F) (30 mg, 0.1 mmol) in acetonitrile (1 mL), andstirred for 24 h at 80° C. The reaction mixture was concentrated,diluted with EtOAc (5 mL) and washed with H₂O (5 mL). The organicextract was dried over MgSO₄ and concentrated to give the subtitlecompound, which was used without further purification. MS calculated forC₂₂H₂₃F₂NO₂+H: 372, observed: 372.

Step B.6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 10, Step F. Thecrude product was purified by reverse-phase liquid chromatography toafford the title compound. MS calculated for C₁₇H₁₅F₂N+H: 272, observed:272.

Example 13 5-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-m-Tolyl-acrylic acid ethyl ester. (Scheme 3)

KHMDS (4.0 g, 20.0 mmol) was added to a solution ofethyl[bis(2,2,2-trifluoro-ethoxy)phosphinyl]acetate (4.7 mL, 20.0 mmol)and 18-crown-6 (10.6 g, 40.0 mmol) in THF (200 mL) at −78° C., andstirred for 30 minutes. m-Tolualdehyde (2.1 mL, 18 mmol) was added andthe reaction mixture was stirred for 3 hours from −78° C. to roomtemperature. The reaction was quenched with aqueous hydrochloric acid(1M solution, 100 mL), and the product was extracted with EtOAc (3×100mL). The organic extracts were washed with brine (100 mL), dried overMgSO₄, and concentrated to afford the subtitle compound, which was usedwithout further purification. MS calculated for C₁₂H₁₄O₂+H: 191,observed: 191.

Step B. 1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-m-tolyl-acrylic acid ethyl ester (18.0 mmol). The crudeproduct was purified by column chromatography (SiO₂) using a 10-50%ethyl acetate-hexanes gradient to afford 4.7 g (81%—two steps) of thesubtitle compound. MS calculated for C₂₁H₂₅NO₂+H: 324, observed: 324.

Step C. 1-Benzyl 4-m-tolyl-pyrrolidine-3-carboxylic Acid

1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (4.6 g,14.5 mmol) was suspended in aqueous HCl (73 mL, 18.0 M), and stirredovernight at 80° C. The reaction mixture was concentrated via rotaryevaporation and placed on the vacuum line. MS calculated forC₁₉H₂₁NO₂+H: 296, observed: 296.

Step D.2-Benzyl-5-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

DMF (16 drops) and oxalyl chloride (4.1 mL, 43.5 mmol) were added to asolution of 1-benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid (4.3 g,14.5 mmol) in CH₂Cl₂ (29 mL) at 0° C. The reaction mixture was stirredovernight at room temperature, then concentrated via rotary evaporation,and placed on the vacuum line without any purification.

A solution of the acid chloride intermediate in CH₂Cl₂ (29 mL) was addedslowly to a solution of AlCl₃ (4.9 g, 43.5 mmol) in CH₂Cl₂ (29 mL) at 0°C. The reaction mixture was stirred for 3 hours from 0° C. to roomtemperature, then quenched via the slow addition of a saturated solutionof sodium bicarbonate (290 mL). The product was extracted with CH₂Cl₂(3×100 mL). The organic extracts were washed with brine, dried overMgSO₄, and concentrated. The crude product was purified by columnchromatography (SiO₂) using a 10-50% ethyl acetate-hexanes gradient toafford 0.91 g (23%—two steps) of the subtitle compound and 0.12 g(3%—two steps) of the regioisomeric2-benzyl-7-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one.MS calculated for C₁₉H₁₉NO+H: 278, observed: 278.

Step E.2-Benzyl-5-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing2-benzyl-5-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(3.2 mmol). The crude product was purified by silica plug eluting withethyl acetate-hexanes (3/1, v/v) to afford 0.88 g (98%) of the subtitledcompound. MS calculated for C₂₀H₂₁N+H: 276, observed: 276.

Step F. 5-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step Eutilizing2-benzyl-5-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(3.2 mmol). An aliquot of the crude product was purified byreverse-phase liquid chromatography to afford the title compound. ¹H NMR(d₆-DMSO 300 MHz) δ 6.98 (m, 3H), 3.55 (m, 1H), 3.25 (m, 2H), 2.85 (m,3H), 2.45 (m, 1H), 2.24 (s, 3H), 1.22 (d, 3H) ppm. MS calculated forC₁₃H₁₇N+H: 188, observed: 188.

Example 14 4-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-o-Tolyl-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing o-tolualdehyde (9.0 mmol). The crude product was obtainedwithout further purification. MS calculated for C₁₂H₁₄O₂+H: 191,observed: 191.

Step B. 1-Benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-O-tolyl-acrylic acid ethyl ester (9.0 mmol). The crudeproduct was purified by column chromatography (SiO₂) using a 10-50%ethyl acetate-hexanes gradient to afford 2.3 g (79%—two steps) of thesubtitle compound. MS calculated for C₂₁H₂₅NO₂+H: 324, observed: 324.

Step C. 1-Benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid ethyl ester(7.1 mmol). The crude product was obtained without further purification.MS calculated for C₁₉H₂₁NO₂+H: 296, observed: 296.

Step D. 2-Benzyl-4-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid (7.1 mmol).The crude product was purified by column chromatography (SiO₂) using a15-60% EtOAc—hexanes gradient to afford 0.73 g (37%—two steps) of thesubtitle compound. MS calculated for C₁₉H₁₉NO+H: 278, observed: 278.

Step E.2-Benzyl-4-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing2-benzyl-4-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(2.6 mmol). The crude product was purified by silica plug eluting withEtOAc—hexanes (3/1, v/v) to afford the subtitled compound. MS calculatedfor C₂₀H₂₁N+H: 276, observed: 276.

Step F. 4-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step Eutilizing2-benzyl-4-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(2.6 mmol). An aliquot of the crude product was purified byreverse-phase liquid chromatography to afford the title compound. ¹H NMR(d₆-DMSO 300 MHz) δ 7.10 (m, 1H), 6.98 (m, 2H), 3.72 (m, 1H), 3.48 (m,1H), 3.22 (m, 1H), 2.97 (m, 2H), 2.72 (m, 1H), 2.45 (m, 1H), 2.21 (s,3H), 1.22 (d, 3H) ppm. MS calculated for C₁₃H₁₇N+H: 188, observed: 188.

Example 15 6-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-p-Tolyl-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing p-tolualdehyde (4.5 mmol). The crude product was obtainedwithout further purification. MS calculated for C₁₂H₁₄O₂+H: 191,observed: 191.

Step B. 1-Benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-p-tolyl-acrylic acid ethyl ester (4.5 mmol). The crudeproduct was purified by column chromatography (SiO₂) using a 10-60%EtOAc—hexanes gradient to afford 1.15 g (79%—two steps) of the subtitlecompound. MS calculated for C₂₁H₂₅NO₂+H: 324, observed: 324.

Step C. 1-Benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid ethyl ester(3.6 mmol). The crude product was obtained without further purification.MS calculated for C₁₉H₂₁NO₂+H: 296, observed: 296.

Step D.2-Benzyl-6-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid (3.6 mmol).The crude product was purified by column chromatography (SiO₂) using a15-60% EtOAc—hexanes gradient to afford 0.50 g (50%—two steps) of thesubtitle compound. MS calculated for C₁₉H₁₉NO+H: 278, observed: 278.

Step E.2-Benzyl-6-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing2-benzyl-6-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(1.8 mmol). The crude product was purified by silica plug eluting withEtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculatedfor C₂₀H₂₁N+H: 276, observed: 276.

Step F. 6-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step Eutilizing2-benzyl-6-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(1.8 mmol). An aliquot of the crude product was purified byreverse-phase liquid chromatography to afford the title compound. ¹H NMR(d₆-DMSO 300 MHz) δ 7.00 (m, 3H), 3.61 (m, 1H), 3.30 (m, 2H), 2.9 (m,3H), 2.42 (m, 1H), 2.27 (s, 3H), 1.22 (d, 3H) ppm. MS calculated forC₁₃H₁₇N+H: 188, observed: 188.

Example 16 7-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.2-Benzyl-7-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene.(Scheme 3)

The subtitle compound was prepared by the method of Example 1, Step Dutilizing2-benzyl-7-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(from Example 13, Step D, regioisomer) (0.43 mmol). The crude productwas purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) toafford the subtitle compound. MS calculated for C₂₀H₂₁N+H: 276,observed: 276.

Step B. 7-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step Eutilizing2-benzyl-7-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.43 mmol). An aliquot of the crude product was purified byreverse-phase liquid chromatography to afford the title compound. ¹H NMR(d₆-DMSO 300 MHz) δ 7.05 (m, 3H), 3.62 (m, 1H), 3.39 (m, 2H), 2.99 (m,3H), 2.77 (m, 1H), 2.28 (s, 3H), 1.27 (d, 3H) ppm. MS calculated forC₁₃H₁₇N+H: 188, observed: 188.

Example 17 4-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-o-Fluoro-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing 2-fluorobenzaldehyde (9.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₁FO₂+H:195, observed: 195.

Step B. 1-Benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-o-fluoro-acrylic acid ethyl ester (9.0 mmol). The crudeproduct was purified by column chromatography (SiO₂) using a 10-50%EtOAc—hexanes gradient to afford the subtitle compound in quantitativeyield. MS calculated for C₂₀H₂₂FNO₂+H: 328, observed: 328.

Step C. 1-Benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid ethyl ester(9.0 mmol). The crude product was obtained without further purification.MS calculated for C₁₈H₁₈FNO₂+H: 300, observed: 300.

Step D.2-Benzyl-4-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid (9.0 mmol).The crude product was purified by column chromatography (SiO₂) using a0-50% EtOAc—hexanes gradient to afford 0.59 g (23%—four steps) of thesubtitle compound. MS calculated for C₁₈H₁₆FNO+H: 282, observed: 282.

Step E.2-Benzyl-4-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing 2-benzyl-4-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.1 mmol). The crudeproduct was purified by silica plug eluting with EtOAc—hexanes (3/1,v/v) to afford the subtitle compound. MS calculated for C₂₉H₁₈FN+H: 280,observed: 280.

Step F. 4-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step Eutilizing 2-benzyl-4-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (2.1 mmol). An aliquot of thecrude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.26 (m, 1H), 6.99(m, 2H), 3.83 (m, 1H), 3.39 (m, 2H), 2.99 (m, 3H), 2.51 (m, 1H), 1.26(d, 3H) ppm. MS calculated for C₁₂H₁₄FN+H: 192, observed: 192.

Example 18 5-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-m-Fluoro-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing m-fluorobenzaldehyde (18.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₁FO₂+H:195, observed: 195.

Step B. 1-Benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-m-fluoro-acrylic acid ethyl ester (18.0 mmol). The crudeproduct was purified by column chromatography (SiO₂) using a 10-50%EtOAc—hexanes gradient to afford the subtitle compound in quantitativeyield. MS calculated for C₂₀H₂₂FNO₂+H: 328, observed: 328.

Step C. 1-Benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid ethyl ester(18.0 mmol). The crude product was obtained without furtherpurification. MS calculated for C₁₈H₁₈FNO₂+H: 300, observed: 300.

Step D.2-Benzyl-5-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid (18.0 mmol).The crude product was purified by column chromatography (SiO₂) using a0-50% EtOAc—hexanes gradient to afford 2.7 g (53%—four steps) of thesubtitle compound. MS calculated for C₁₈H₁₆FNO+H: 282, observed: 282.

Step E.2-Benzyl-5-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing 2-benzyl-5-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.6 mmol). The crudeproduct was purified by silica plug eluting with EtOAc—hexanes (3/1,v/v) to afford the subtitle compound. MS calculated for C₂₉H₁₈FN+H: 280,observed: 280.

Step F. 5-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step Eutilizing 2-benzyl-5-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (9.6 mmol). An aliquot of thecrude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.18 (m, 1H), 7.02(m, 2H), 3.68 (m, 1H), 3.33 (m, 2H), 2.98 (m, 3H), 2.45 (m, 1H), 1.21(d, 3H) ppm. MS calculated for C₁₂H₁₄FN+H: 192, observed: 192.

Example 19 6-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-p-Fluoro-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing p-fluorobenzaldehyde (9.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₁FO₂+H:195, observed: 195.

Step B. 1-Benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-p-fluoro-acrylic acid ethyl ester (9.0 mmol). The crudeproduct was purified by column chromatography (SiO₂) using a 10-50%EtOAc—hexanes gradient to afford the subtitle compound in quantitativeyield. MS calculated for C₂₀H₂₂FNO₂+H: 328, observed: 328.

Step C. 1-Benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid ethyl ester(9.0 mmol). The crude product was obtained without further purification.MS calculated for C₁₈H₁₈FNO₂+H: 300, observed: 300.

Step D.2-Benzyl-6-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid (9.0 mmol).The crude product was purified by column chromatography (SiO₂) using a0-50% EtOAc—hexanes gradient to afford 1.12 g (44%—four steps) of thesubtitle compound. MS calculated for C₁₈H₁₆FNO+H: 282, observed: 282.

Step E.2-Benzyl-6-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing 2-benzyl-6-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (4.0 mmol). The crudeproduct was purified by silica plug eluting with EtOAc—hexanes (3/1,v/v) to afford the subtitle compound. MS calculated for C₂₉H₁₈FN+H: 280,observed: 280.

Step F. 6-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step Eutilizing 2-benzyl-5-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.0 mmol). An aliquot of thecrude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.18 (m, 1H), 6.99(m, 2H), 3.62 (m, 1H), 3.29 (m, 2H), 2.87 (m, 3H), 2.45 (m, 1H), 1.22(d, 3H) ppm. MS calculated for C₁₂H₁₄FN+H: 192, observed: 192.

Example 20 5-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-m-Chloro-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing 3-chlorobenzaldehyde (9.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₁ClO₂+H:211, observed: 211.

Step B. 1-Benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-m-chloro-acrylic acid ethyl ester (9.0 mmol). The crudeproduct was purified by column chromatography (SiO₂) using a 10-50%EtOAc—hexanes gradient to afford the subtitle compound in quantitativeyield. MS calculated for C₂₀H₂₂ClNO₂+H: 344, observed: 344.

Step C. 1-Benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid ethyl ester(9.0 mmol). The crude product was obtained without further purification.MS calculated for C₁₈H₁₈ClNO₂+H: 316, observed: 316.

Step D.2-Benzyl-5-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid (9.0 mmol).The crude product was purified by column chromatography (SiO₂) using a0-50% EtOAc—hexanes gradient to afford 0.59 g (22%—four steps) of thesubtitle compound and 0.20 g (8%—four steps) of the regioisomeric2-benzyl-7-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one.MS calculated for C₁₈H₁₆ClNO+H: 298, observed: 298.

Step E.2-Benzyl-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing2-benzyl-5-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(2.0 mmol). The crude product was purified by silica plug eluting withEtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculatedfor C₁₉H₁₈ClN+H: 296, observed: 296.

Step F.5-Chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

ACE-Cl (1.08 mL, 9.9 mmol) and K₂CO₃ (1.4 g, 9.9 mmol) were added to asolution of 2-benzyl-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (2.0 mmol) in DCE (10 mL) at 0°C. The reaction mixture was stirred for 30 minutes at 0° C., thenovernight at 60° C. The reaction mixture was filtered through celite,the celite was washed with CH₂Cl₂, and the filtrate was concentrated.The carbamate intermediate was dissolved in MeOH (10 mL) and stirred for1 hour at 40° C. The solution was cooled to room temperature andconcentrated via rotary evaporation. MS calculated for C₁₂H₁₂ClN+H: 206,observed: 206.

Step G. N-tert-Butylcarbamate-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

Di-tert-butyl dicarbonate (0.43 g, 2.00 mmol) and DIEA (1.0 mL, 6.0mmol) were added to a solution of5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(2.0 mmol) in CH₂Cl₂ (10 mL) at 0° C. The reaction mixture was stirredfor 2 hours at from 0° C. to room temperature, then quenched withaqueous HCl (10 mL, 0.1 M). The organic extracts were washed with brine,dried over MgSO₄, and concentrated to afford the subtitle compound inquantitative yield. MS calculated for C₁₇H₂₀ClNO₂+H: 306, observed: 306.

Step H. N-tert-Butylcarbamate-5-chloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

N-tert-Butyl carbamate-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.6 g, 2.0 mmol) was dissolvedin EtOAc (10 mL) and purged with N₂. Palladium on carbon (0.2 g, 10 wt.%) was added and the flask was purged with N₂, and then charged with aballoon of H₂. The reaction mixture was stirred for 2 hours at roomtemperature then filtered through celite. The celite was washed withEtOAc, and the filtrate was concentrated to afford the subtitle compoundin quantitative yield. MS calculated for C₁₇H₂₂ClNO₂+H: 308, observed:308.

Step I. 5-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

N-tert-Butylcarbamate-5-chloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(10 mg, 0.03 mmol) was dissolved in an HCl solution (3 mL, 4 M indioxane). The reaction was stirred for 2 hours at room temperature, andthen concentrated to afford the title compound. An aliquot of the crudeproduct was purified by reverse-phase liquid chromatography to affordthe title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.21 (m, 3H), 3.68 (m,1H), 3.31 (m, 2H), 2.92 (m, 3H), 2.45 (m, 1H), 1.22 (d, 3H) ppm. MScalculated for C₁₂H₁₄ClN+H: 208, observed: 208.

Example 215-Methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 3)

Ethyl chloroformate (0.29 mL, 3.0 mmol) and DIEA (1.6 mL, 9.0 mmol) wereadded to a solution of5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (fromExample 13, Step F) (0.56 g, 3.0 mmol) in CH₂Cl₂ (15 mL) at 0° C. Thereaction was stirred for 2 hours from 0° C. to room temperature. Thereaction was quenched with aqueous HCl (15 mL, 1 M). The desired productwas extracted with CH₂Cl₂ (3×15 mL). The organic extracts were washedwith brine, dried over MgSO₄, and concentrated. The crude product waspurified by column chromatography (SiO₂) using a 10-60% EtOAc—hexanesgradient to afford 0.36 g (46%) of the subtitle compound. MS calculatedfor C₁₆H₂₁NO₂+H: 260, observed: 260.

Step B.N-Ethylcarbamate-5-methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

NCS (27 mg, 0.2 mmol) and acetic acid (1 mL) were added to a solution ofN-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(50 mg, 0.2 mmol) in DCE (1 mL). The reaction solution was stirred for 3hours at 60° C. The reaction was diluted with CH₂Cl₂ (3 mL) and H₂O (3mL) and filtered through an Extrelut column. The column was washed withCH₂Cl₂ and the filtrate was concentrated. The crude product was purifiedby column chromatography (SiO₂) using a 0-60% ethyl acetate-hexanesgradient to afford the subtitle compound. MS calculated forC₁₆H₂₀ClNO₂+H: 294, observed: 294.

Step C.5-Methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step Butilizing N-Ethylcarbamate-5-methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified byreverse-phase liquid chromatography to afford the title compound. MScalculated for C₁₃H₁₆ClN+H: 222, observed: 222.

Example 225-Methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 3)

NBS (34 mg, 0.2 mmol) was added to a solution ofN-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 21, Step A) (50 mg, 0.2 mmol) in acetonitrile (1 mL), andstirred overnight at room temperature. The reaction was diluted withCH₂Cl₂ (3 mL) and H₂O (3 mL) and filtered through an Extrelut column.The column was washed with CH₂Cl₂ and the filtrate was concentrated. Thecrude product was purified by column chromatography (SiO₂) using a 0-50%EtOAc—hexanes gradient to afford the subtitle compound. MS calculatedfor C₁₆H₂₀BrNO₂+H: 338, observed: 338.

Step C.5-Methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-Ethylcarbamate-5-methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.29 (s, 1H), 7.12(s, 1H), 3.70 (m, 3H), 2.92 (m, 3H), 2.45 (m, 1H), 2.29 (s, 3H), 1.22(d, 3H) ppm. MS calculated for C₁₃H₁₆BrN+H: 266, observed: 266.

Example 235-Chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 3)

The subtitle compound was prepared by the method of Example 21, Step Autilizing 6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 15, Step F) (1.8 mmol). The crude product was purified bycolumn chromatography (SiO₂) using a 10-60% EtOAc—hexanes gradient toafford 0.25 g (54%) of the subtitle compound. MS calculated forC₁₆H₂₁NO₂+H: 260, observed: 260.

Step B.N-Ethylcarbamate-5-chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 21, Step ButilizingN-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.2 mmol). The crude product was purified by column chromatography(SiO₂) using a 0-60 EtOAc—hexanes gradient to afford the subtitlecompound. MS calculated for C₁₆H₂₀ClNO₂+H: 294, observed: 294.

Step C.5-Chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-Ethylcarbamate-5-chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.21 (s, 1H), 7.10(s, 1H), 3.61 (m, 1H), 3.29 (m, 2H), 2.88 (m, 3H), 2.45 (m, 1H), 2.29(s, 3H), 1.22 (d, 3H) ppm. MS calculated for C₁₃H₁₆ClN+H: 222, observed:222.

Example 245-Bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 3)

The subtitle compound was prepared by the method of Example 22, Step AutilizingN-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 23, Step A) (0.2 mmol). The crude product was purified bycolumn chromatography (SiO₂) using a 0-50% EtOAc—hexanes gradient toafford the subtitle compound. MS calculated for C₁₆H₂₀BrNO₂+H: 338,observed: 338.

Step B.5-Bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-Ethylcarbamate-5-bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.The crude product was purified by reverse-phase liquid chromatography toafford the title compound. MS calculated for C₁₃H₁₆BrN+H: 266, observed:266.

Example 254-Chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-4-chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

N-chlorosuccinimide (0.39 g, 2.9 mmol) and acetic acid (3 mL) were addedto a solution ofN-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 2, Step A) (0.80 g, 2.9 mmol) in DCE (3 mL). The resultingsolution was stirred for 3 hours at 60° C. The reaction mixture wascooled to room temperature, diluted with CH₂Cl₂ (50 mL), and washed withH₂O (50 mL). The organic extract was dried over MgSO₄ and concentrated.The crude product was purified by column chromatography (SiO₂) using a0-35% EtOAc—hexanes gradient to afford 50 mg (6%) of the subtitlecompound (The major product isN-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, 78%). MS calculated for C₁₆H₂₀ClNO₃+H: 310, observed:310.

Step B.4-Chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-Ethylcarbamate-4-chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.16 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ7.08 (d, 1H), 6.98 (d, 1H), 3.81 (s, 3H), 3.64 (m, 1H), 3.47 (m, 1H),3.29 (m, 1H), 2.91 (m, 3H), 2.45 (m, 1H), 1.21 (d, 3H) ppm. MScalculated for C₁₃H₁₆ClNO+H: 238, observed: 238.

Example 265,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(3,4-Dichloro-phenyl)-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing 3,4-dichlorobenzaldehyde (9.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₀Cl₂O₂+H:245, observed: 245.

Step B. 1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acidethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-(3,4-dichloro-phenyl)-acrylic acid ethyl ester (9.0 mmol).The crude product was purified by column chromatography (SiO₂) using a10-50% EtOAc—hexanes gradient to afford the subtitle compound inquantitative yield. MS calculated for C₂₀H₂₂Cl₂NO₂+H: 378, observed:378.

Step C. 1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acidethyl ester (9.0 mmol). The crude product was obtained without furtherpurification. MS calculated for C₁₈H₁₈Cl₂NO₂+H: 350, observed: 350.

Step D.2-Benzyl-5,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid(9.0 mmol). The crude product was purified by column chromatography(SiO₂) using a 0-50% EtOAC—hexanes gradient to afford 0.59 g (20%—foursteps) of the subtitle compound and 0.30 g (10%—four steps) of theregioisomeric2-benzyl-6,7-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one.MS calculated for C₁₈H₁₆Cl₂NO+H: 332, observed: 332.

Step E.2-Benzyl-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing2-benzyl-5,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(0.9 mmol). The crude product was purified by silica plug eluting withEtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculatedfor C₁₉H₁₈Cl₂N+H: 330, observed: 330.

Step F.5,6-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Futilizing2-benzyl-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.9 mmol). The crude product was obtained without further purification.MS calculated for C₁₂H₁₂Cl₂N+H: 240, observed: 240.

Step G. N-tert-Butylcarbamate-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Gutilizing5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.9 mmol). The crude product was obtained without further purification.MS calculated for C₁₇H₂₀Cl₂NO₂+H: 340, observed: 340.

Step H. N-tert-Butylcarbamate-5,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Hutilizing N-tert-butylcarbamate-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.9 mmol). The crude product was obtained without further purification.MS calculated for C₁₇H₂₂Cl₂NO₂+H: 342, observed: 342.

Step I.5,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 20, Step Iutilizing N-tert-butylcarbamate-5,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene.An aliquot of the crude product was purified by reverse-phase liquidchromatography to afford the title compound. MS calculated forC₁₂H₁₄Cl₂N+H: 242, observed: 242.

Example 276,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.2-Benzyl-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene.(Scheme 3)

The subtitle compound was prepared by the method of Example 1, Step Dutilizing 2-benzyl-6,7-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 26, StepD, regioisomer) (1.8 mmol). The crude product was purified by silicaplug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitlecompound. MS calculated for C₁₉H₁₈Cl₂N+H: 330, observed: 330.

Step B.6,7-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Futilizing2-benzyl-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(1.8 mmol). The crude product was obtained without further purification.MS calculated for C₁₂H₁₂Cl₂N+H: 240, observed: 240.

Step C. N-tert-Butylcarbamate-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Gutilizing 6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol). The crude productwas obtained without further purification. MS calculated forC₁₇H₂₀Cl₂NO₂+H: 340, observed: 340.

Step D. N-tert-Butylcarbamate-6,7-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Hutilizing N-tert-butylcarbamate-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(1.8 mmol). The crude product was obtained without further purification.MS calculated for C₁₇H₂₂Cl₂NO₂+H: 342, observed: 342.

Step E.6,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 20, Step Iutilizing N-tert-butylcarbamate-6,7-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene.An aliquot of the crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ7.46 (d, 1H), 7.20 (d, 1H), 3.68 (m, 1H), 3.51 (m, 1H), 3.23 (m, 1H),3.08 (m, 1H), 3.88 (m, 3H), 1.37 (d, 3H) ppm. MS calculated forC₁₂H₁₄Cl₂N+H: 242, observed: 242.

Example 284,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(2,4-Dichloro-phenyl)-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing 3,4-dichlorobenzaldehyde (18.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₀Cl₂O₂+H:245, observed: 245.

Step B. 1-Benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acidethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-(2,4-dichloro-phenyl)-acrylic acid ethyl ester (18.0 mmol).The crude product was purified by column chromatography (SiO₂) using a10-50% EtOAc—hexanes gradient to afford the subtitle compound inquantitative yield. MS calculated for C₂₀H₂₂Cl₂NO₂+H: 378, observed:378.

Step C. 1-Benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acidethyl ester (18.0 mmol). The crude product was obtained without furtherpurification. MS calculated for C₁₈H₁₈Cl₂NO₂+H: 350, observed: 350.

Step D.2-Benzyl-4,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid(18.0 mmol). The crude product was purified by column chromatography(SiO₂) using a 0-50% EtOAc—hexanes gradient to afford 1.5 g (25%—foursteps) of the subtitle compound. MS calculated for C₁₈H₁₆Cl₂NO+H: 332,observed: 332.

Step E.2-Benzyl-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing2-benzyl-4,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(4.5 mmol). The crude product was purified by silica plug eluting withEtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculatedfor C₁₉H₁₈Cl₂N+H: 330, observed: 330.

Step F.4,6-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Futilizing 2-benzyl-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.5 mmol). The crude productwas obtained without further purification. MS calculated forC₁₂H₁₂Cl₂N+H: 240, observed: 240.

Step G. N-tert-Butylcarbamate-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Gutilizing4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(4.5 mmol). The crude product was obtained without further purification.MS calculated for C₁₇H₂₀Cl₂NO₂+H: 340, observed: 340.

Step H. N-tert-Butylcarbamate-4,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Hutilizing N-tert-butylcarbamate-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.9 mmol) to afford 0.33 g (22%—4 steps) of the subtitle compound. MScalculated for C₁₇H₂₂Cl₂NO₂+H: 342, observed: 342.

Step I.4,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.

The title compound was prepared by the method of Example 20, Step Iutilizing N-tert-butylcarbamate-4,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene.An aliquot of the crude product was purified by reverse-phase liquidchromatography to afford the title compound. MS calculated forC₁₂H₁₄Cl₂N+H: 242, observed: 242.

Example 295-Ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

BBr₃ (0.3 mL, 0.30 mmol, 1 M in CH₂Cl₂) was added to a solution ofN-Ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 3, Step A) (46 mg, 0.15 mmol) at 0° C., and stirredovernight at room temperature. The reaction solution was quenched withH₂O and filtered through an Extrelut column. The column was washed withCH₂Cl₂, and the filtrate was concentrated. The crude product wasobtained without further purification. MS calculated for C₁₅H₁₈ClNO₃+H:296, observed: 296.

Step B.N-Ethylcarbamate-5-ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Bromoethane (17 mL, 0.23 mmol) and K₂CO₃ (105 mg, 0.75 mmol) were addedto a solution ofN-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(44 mg, 0.15 mmol) in CH₃CN (1.5 mL). The reaction was stirred overnightat 70° C., diluted with H₂O and CH₂Cl₂, and filtered through an Extrelutcolumn. The column was washed with CH₂Cl₂ and the filtrate wasconcentrated. The crude product was obtained without furtherpurification. MS calculated for C₁₇H₂₂ClNO₃+H: 324, observed: 324.

Step C.5-Ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.15 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ7.18 (s, 1H), 7.00 (s, 1H), 4.09 (m, 2H), 3.68 (m, 1H), 3.31 (m, 2H),2.99 (m, 3H), 2.45 (m, 1H), 1.33 (t, 3H), 1.21 (d, 3H) ppm. MScalculated for C₁₄H₁₈ClNO+H: 252, observed: 252.

Example 305-Methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

NBS (70 mg, 0.4 mmol) was added to a solution ofN-methylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 2, step A) (0.1 g, 0.36 mmol) in CH₃CN (3.6 mL), andstirred overnight at room temperature. The reaction was diluted with H₂Oand EtOAc and filtered through an Extrelut column. The column was washedwith EtOAc and the filtrate was concentrated to afford 120 mg (94%) ofthe subtitle compound. MS calculated for C₁₆H₂₀BrNO₃+H: 342, observed:342.

Step B.5-Methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.17 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ7.29 (s, 1H), 6.93 (s, 1H), 3.81 (s, 3H), 3.61 (m, 1H), 3.28 (m, 2H),2.98 (m, 1H), 2.83 (m, 2H), 2.45 (m, 1H), 1.33 (t, 3H), 1.21 (d, 3H)ppm. MS calculated for C₁₃H₁₆BrNO+H: 282, observed: 282.

Example 315-Hydroxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-hydroxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

The subtitle compound was prepared by the method of Example 29, Step AutilizingN-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 30, Step A) (0.09 mmol). The crude product was obtainedwithout further purification. MS calculated for C₁₅H₁₈BrNO₃+H: 340,observed: 340.

Step B.5-Hydroxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step Butilizing N-ethylcarbamate-5-hydroxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.09 mmol). The crude product waspurified by reverse-phase liquid chromatography to afford the titlecompound. MS calculated for C₁₂H₁₄BrNO+H: 268, observed: 268.

Example 325-Methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

Thiophene-2-boronic acid (44 mg, 0.34 mmol), Pd(PPh₃)₄ (19 mg, 0.02mmol), K₂CO₃ (71 mg, 0.51 mmol), and H₂O (0.17 mL) were added to asolution ofN-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 30, Step A) (60 mg, 0.17 mmol) in dioxane (3 mL) andstirred overnight at 100° C. The reaction mixture was diluted with EtOACand H₂O, and filtered through an Extrelut column. The column was washedwith EtOAc, and the filtrate was concentrated. The crude product waspurified via a silica plug eluting with Hexanes/EtOAc (2/1, v/v). MScalculated for C₂₀H₂₅NO₃S+H: 358, observed: 358.

Step B.5-Methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.17 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz)67.52 (d, 1H), 7.49 (d, 1H), 7.41 (s, 1H), 7.10 (t, 1H), 6.97 (s, 1H),3.88 (s, 3H), 3.66 (m, 1H), 3.31 (m, 2H), 3.00 (m, 1H), 2.88 (m, 2H),2.45 (m, 1H), 1.29 (d, 3H) ppm. MS calculated for C₁₇H₁₉NOS+H: 286,observed: 286.

Example 335-Methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

CuCN (68 mg, 0.85 mmol) was added to a solution ofN-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 30, Step A) (60 mg, 0.17 mmol) in DMF (1.7 mL), andstirred overnight at 100° C. The reaction mixture was diluted with EtOACand H₂O, and filtered through an Extrelut column. The column was washedwith EtOAc, and the filtrate was concentrated. The crude product waspurified via a silica plug eluting with Hexanes/EtOAc (2/1, v/v). MScalculated for C₁₇H₂₀N₂O₃+H: 301, observed: 301.

Step B.5-Methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.17 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ7.44 (s, 1H), 7.04 (s, 1H), 3.88 (s, 3H), 3.65 (m, 1H), 3.23 (m, 2H),2.88 (m, 1H), 2.78 (m, 2H), 2.40 (m, 1H), 1.21 (d, 3H) ppm. MScalculated for C₁₄H₁₆N₂O+H: 229, observed: 229.

Example 344,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-Bromo-4,5-dimethoxy-1-indanone. (Scheme 3)

The subtitle compound was prepared by the method of Example 1, Step Autilizing 4,5-dimethoxy-1-indanone (26.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₁BrO₃+H:271, observed: 271.

Step B. 4,5-Dimethoxy-inden-1-one

The subtitle compound was prepared by the method of Example 1, Step Butilizing 3-bromo-4,5-dimethoxy-1-indanone (26.0 mmol). The crudeproduct was obtained without further purification. MS calculated forC₁₁H₁₀O₃+H: 191, observed: 191.

Step C.2-Benzyl-4,5-dimethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 4,5-dimethoxy-inden-1-one (26.0 mmol). The crude product waspurified by silica plug eluting with hexanes/EtOAc(3/1, v/v) to afford4.2 g (50%-3 steps) of the subtitle compound. MS calculated forC₂₀H₂₁NO₃+H: 324, observed: 324.

Step D.2-Benzyl-4,5-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step Dutilizing 2-benzyl-4,5-dimethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (13.0 mmol). The crudeproduct was purified by silica plug eluting with hexanes/EtOAc (3/1,v/v) to afford the subtitle compound in quantitative yield. MScalculated for C₂₁H₂₃NO₂+H: 322, observed: 322.

Step E.4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step Eutilizing2-benzyl-4,5-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(13.0 mmol). The crude product was obtained without furtherpurification. MS calculated for C₁₄H₁₉NO₂+H: 234, observed: 234.

Step F.N-Ethylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 2, Step Autilizing4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (13.0mmol). The crude product was purified by column chromatography (SiO₂)using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound. MScalculated for C₁₇H₂₃NO₄+H: 306, observed: 306.

Step G.4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.03 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ6.88 (d, 1H), 6.79 (d, 1H), 3.72 (m, 7H), 3.32 (m, 1H), 3.21 (m, 1H),2.84 (m, 3H), 2.40 (m, 1H), 1.19 (d, 3H) ppm. MS calculated forC₁₄H₁₉NO₂+H: 234, observed: 234.

Example 354,5-Dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-4,5-dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 3)

The subtitle compound was prepared by the method of Example 3, Step Autilizing N-ethylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 34, Step F) (0.58mmol). The crude product was obtained without further purification. MScalculated for C₁₇H₂₂ClNO₄+H: 340, observed: 340.

Step B.5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-4,5-dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.12 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ6.88 (d, 1H), 6.79 (d, 1H), 3.72 (m, 7H), 3.32 (m, 1H), 3.21 (m, 1H),2.84 (m, 3H), 2.40 (m, 1H), 1.19 (d, 3H) ppm. MS calculated forC₁₄H₁₈ClNO₂+H: 268, observed: 268.

Example 364,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-Bromo-5,6-dimethoxy-1-indanone. (Scheme 3)

The subtitle compound was prepared by the method of Example 1, Step Autilizing 5,6-dimethoxy-1-indanone (52.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₁BrO₃+H:271, observed: 271.

Step B. 5,6-Dimethoxy-inden-1-one

The subtitle compound was prepared by the method of Example 1, Step Butilizing 3-bromo-5,6-dimethoxy-1-indanone (52.0 mmol). The crudeproduct was obtained without further purification. MS calculated forC₁₁H₁₀O₃+H: 191, observed: 191.

Step C.2-Benzyl-5,6-dimethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 5,6-dimethoxy-inden-1-one (52.0 mmol). The crude product waspurified by silica plug eluting with hexanes/EtOAc (3/1, v/v) to affordthe subtitle compound. MS calculated for C₂₀H₂₁NO₃+H: 324, observed:324.

Step D.2-Benzyl-5,6-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step Dutilizing 2-benzyl-5,6-dimethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (3.1 mmol). The crudeproduct was purified by silica plug eluting with hexanes/EtOAc (3/1,v/v) to afford the subtitle compound in quantitative yield. MScalculated for C₂₁H₂₃NO₂+H: 322, observed: 322.

Step E.5,6-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step Eutilizing2-benzyl-5,6-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(3.1 mmol). The crude product was obtained without further purification.MS calculated for C₁₄H₁₉NO₂+H: 234, observed: 234.

Step F.N-tert-Butylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 20, Step Gutilizing5,6-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (3.1mmol). The crude product was purified by column chromatography (SiO₂)using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound. MScalculated for C₁₉H₂₇NO₄+H: 334, observed: 334.

Step G.4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 20, Step HutilizingN-tert-butylcarbamate-5,6-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.15 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ6.92 (s, 1H), 6.80 (s, 1H), 3.72 (m, 7H), 3.55 (m, 1H), 3.21 (m, 4H),2.65 (m, 1H), 1.26 (d, 3H) ppm. MS calculated for C₁₄H₁₉NO₂+H: 234,observed: 234.

Example 375-Methoxy-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.2-Benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]inden-8-ol.(Scheme 1)

NaBH₄ (0.27 g, 6.8 mmol) was added to a solution of2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(from Example 1, Step C) (1.0 g, 3.4 mmol) in MeOH (17 mL), and stirredfor 2 hours at room temperature. The reaction solution was concentratedvia rotary evaporation and the residue dissolved in EtOAc. The organicsolution was washed with a saturated aqueous NaHCO₃ solution and brine,dried over MgSO₄, and concentrated. The crude product was obtainedwithout further purification. MS calculated for C₁₉H₂₁NO₂+H: 296,observed: 296.

Step B. 2-Benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

InCl₃ (0.38 g, 1.7 mmol) and chlorodiphenylsilane (1.3 mL, 6.8 mmol)were added to a solution of2-benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]inden-8-ol(3.4 mmol) in DCE (17 mL), and stirred overnight at 60° C. The reactionmixture was washed with H₂O, a saturated aqueous NaHCO₃ solution andbrine. The organic extracts were dried over MgSO₄ and concentrated. Thecrude product was obtained without further purification. MS calculatedfor C₁₉H₂₁NO+H: 280, observed: 280.

Step C. 5-Methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step Eutilizing 2-benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(3.4 mmol). The crude product was obtained without further purification.MS calculated for C₁₂H₁₅NO+H: 190, observed: 190.

Step D.N-Ethylcarbamate-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 2, Step Autilizing 5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[112-c]pyrrole (3.4mmol). The crude product was purified by column chromatography (SiO₂)using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound. MScalculated for C₁₅H₁₉NO₃+H: 262, observed: 262.

Step E.N-Ethylcarbamate-5-methoxy-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 3, Step AutilizingN-ethylcarbamate-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.19 mmol). The crude product was obtained without furtherpurification. MS calculated for C₁₅H₁₈ClNO₃+H: 296, observed: 296.

Step F. 5-Methoxy-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step Butilizing N-ethylcarbamate-5-methoxy-6-chloro-8-1, 2, 3, 3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.19 mmol). The crude product waspurified by reverse-phase liquid chromatography to afford the titlecompound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.17 (s, 1H), 6.97 (s, 1H), 3.81(s, 3H), 3.62 (m, 1H), 3.00 (m, 5H), 2.60 (m, 2H) ppm. MS calculated forC₁₂H₁₄ClNO+H: 224, observed: 224.

Example 384,6-Dichloro-5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-4,6-dichloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

NCS (63 mg, 0.47 mmol) and acetic acid (1 mL) were added to a solutionofN-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 2, Step A) (43 mg, 0.16 mmol) in DCE (1 mL), and thereaction solution was stirred for 3 hours at 70° C. The reaction wasquenched with H₂O and the solution filtered through an Extrelut column.The column was washed with CH₂Cl₂, and the filtrate was concentrated.The subtitle compound was obtained without further purification. MScalculated for C₁₆H₁₉Cl₂NO₃+H: 344, observed: 344.

Step B.4,6-Dichloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-Ethylcarbamate-4,6-dichloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.16 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ7.28 (s, 1H), 3.78 (s, 3H), 3.71 (m, 1H), 3.29 (m, 2H), 2.84 (m, 3H),2.60 (m, 1H), 1.21 (d, 3H) ppm. MS calculated for C₁₃H₁₅Cl₂NO+H: 272,observed: 272.

Example 395-Cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

BBr₃ (1.1 mL, 1.0 M in dichloromethane) was added to a solution ofN-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 2, step A) (0.31 g, 1.1 mmol) in CH₂Cl₂ (10 mL) at 0° C.,and stirred overnight. The excess BBr₃ was quenched with the dropwiseaddition of water (2 mL), and washed with saturated aqueous NaHCO₃ (10mL) and brine (10 mL). The organic extract was dried over MgSO₄ andconcentrated. The subtitle compound was obtained without furtherpurification. MS calculated for C₁₅H₁₉NO₃+H: 262, observed: 262.

Step B.N-Ethylcarbamate-5-cyclopropylmethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

(Bromomethyl)cyclopropane (13 mg, 0.09 mmol) and K₂CO₃ (24 mg, 0.17mmol) were added to a solution ofN-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(23 mg, 0.09 mmol) in CH₃CN, and stirred overnight at 80° C. Thereaction mixture was diluted with H₂O and CH₂Cl₂, and filtered throughan Extrelut column. The column was washed with CH₂Cl₂, and the filtratewas concentrated. The subtitle compound was obtained without furtherpurification. MS calculated for C₁₉H₂₅NO₃+H: 316, observed: 316.

Step C.N-Ethylcarbamate-5-cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

NCS (38 mg, 0.28 mmol) and acetic acid (1 mL) were added to a solutionofN-ethylcarbamate-5-cyclopropylmethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(89 mg, 0.28 mmol) in DCE (2 mL), and the reaction solution was stirredfor 3 hours at 70° C. The reaction was quenched with H₂O and thesolution filtered through an Extrelut column. The column was washed withCH₂Cl₂, and the filtrate was concentrated. The subtitle compound wasobtained without further purification. MS calculated for C₁₉H₂₄ClNO₃+H:350, observed: 350.

Step D.5-Cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.32 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ7.14 (s, 1H), 6.9 (s, 1H), 3.88 (d, 2H), 3.24 (m, 3H), 2.84 (m, 3H),2.45 (m, 1H), 1.21 (m, 4H), 0.58 (d, 2H), 0.32 (d, 2H) ppm. MScalculated for C₁₆H₂₀ClNO+H: 278, observed: 278.

Example 405-Trifluoromethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(3-Trifluoromethoxy-phenyl)-acrylic acid ethyl ester. (Scheme3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing 3-(trifluoromethyl)benzaldehyde (12.5 mmol). The crude productwas obtained without further purification. MS calculated forC₁₂H₁₁F₃O₃+H: 261, observed: 261.

Step B. 1-Benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylicacid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-(3-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (12.5.0mmol). The crude product was purified by column chromatography (SiO₂)using a 10-50% EtOAc—hexanes gradient to afford 3.5 g (72%—two steps) ofthe subtitle compound. MS calculated for C₂, H₂₂F₃NO₃+H: 394, observed:394.

Step C. 1-Benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylicacid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing1-benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acidethyl ester (8.9 mmol). The crude product was obtained without furtherpurification. MS calculated for C₁₉H₁₈F₃NO₃+H: 366, observed: 366.

Step D.2-Benzyl-5-trifluoromethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing1-benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acid(8.9 mmol). The crude product was purified by column chromatography(SiO₂) using a 15-60% EtOAc—hexanes gradient to afford 0.50 g (16%—twosteps) of the subtitle compound. MS calculated for C₁₉H₁₆F₃NO₂+H: 348,observed: 348.

Step E.2-Benzyl-5-trifluoromethoxy-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing2-benzyl-5-trifluoromethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(0.5 mmol). The crude product was purified by silica plug eluting withEtOAc—hexanes (3/1, v/v) to afford the subtitled compound. MS calculatedfor C₂₀H₁₈F₃NO+H: 346, observed: 346.

Step F.5-Trifluoromethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step Eutilizing2-benzyl-5-trifluoromethoxy-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.5 mmol). An aliquot of the crude product was purified byreverse-phase liquid chromatography to afford the title compound. ¹H NMR(d₆-DMSO 300 MHz) δ 7.19 (m, 3H), 3.65 (m, 1H), 3.28 (m, 2H), 2.83 (m,3H), 2.45 (m, 1H), 1.25 (d, 3H) ppm. MS calculated for C₁₃H₁₄F₃NO+H:258, observed: 258.

Example 414,5-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(2,3-Dichloro-phenyl)-acrylic acid ethyl ester

The subtitle compound was prepared by the method of Example 13, Step Autilizing 3,4-dichlorobenzaldehyde (29.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₁H₁₀Cl₂O₂+H:245, observed: 245.

Step B. 1-Benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acidethyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-(2,3-dichloro-phenyl)-acrylic acid ethyl ester (29.0 mmol).The crude product was purified by column chromatography (SiO₂) using a0-70% EtOAc—hexanes gradient to afford 5.3 g (49%—two steps) of thesubtitle compound. MS calculated for C₂₀H₂₂Cl₂NO₂+H: 378, observed: 378.

Step C. 1-Benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acidethyl ester (14.0 mmol). The crude product was obtained without furtherpurification. MS calculated for C₁₈H₁₈Cl₂NO₂+H: 350, observed: 350.

Step D.2-Benzyl-4,5-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid(14.0 mmol). The crude product was purified by column chromatography(SiO₂) using a 0-50% EtOAc—hexanes gradient to afford the subtitlecompound. MS calculated for C₁₈H₁₆Cl₂NO+H: 332, observed: 332.

Step E.2-Benzyl-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step Dutilizing 2-benzyl-4,5-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (14.0 mmol). The crudeproduct was purified by silica plug eluting with EtOAc—hexanes (3/1,v/v) to afford 1.7 g (35%—three steps) of the subtitle compound. MScalculated for C₁₉H₁₈Cl₂N+H: 330, observed: 330.

Step F.4,5-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Futilizing2-benzyl-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(4.9 mmol). The crude product was obtained without further purification.MS calculated for C₁₂H₁₂Cl₂N+H: 240, observed: 240.

Step G. N-Ethylcarbamate-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 2, Step Autilizing4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(4.9 mmol). The crude product was purified by column chromatography(SiO₂) using a 0-60% EtOAc—hexanes gradient to afford 0.32 g (21%—twosteps) of the subtitle compound. MS calculated for C₁₅H₁₅Cl₂NO₂+H: 312,observed: 312.

Step H. N-Ethylcarbamate-4,5-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Hutilizing N-ethylcarbamate-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(1.0 mmol). The crude product was purified by column chromatography(SiO₂) using a 0-60% EtOAc—hexanes gradient to afford 0.10 g (32%) ofthe subtitle compound. MS calculated for C₁₅H₁₇Cl₂NO₂+H: 314, observed:314.

Step I.4,5-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.

The title compound was prepared by the method of Example 3, Step Butilizing N-ethylcarbamate-4,5-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.06 mmol). An aliquot of the crude product was purified byreverse-phase liquid chromatography to afford the title compound. ¹H NMR(d₆-DMSO 300 MHz) δ 7.46 (d, 1H), 7.16 (d, 1H), 3.76 (m, 1H), 3.36 (m,2H), 2.85 (m, 3H), 2.45 (m, 1H), 1.23 (d, 3H) ppm. MS calculated forC₁₂H₁₃Cl₂N+H: 242, observed: 242.

Example 426-Chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(3-Fluoro-4-chloro-phenyl)-acrylic acid methyl ester. (Scheme3)

The subtitle compound was prepared by the method of Example 13, Step Autilizing 3,4-dichlorobenzaldehyde (34.0 mmol). The crude product wasobtained without further purification. MS calculated for C₁₀H₈ClFO₂+H:215, observed: 215.

Step B. 1-Benzyl-4-(3-fluoro-4-chloro-phenyl)-pyrrolidine-3-carboxylicacid methyl ester

The subtitle compound was prepared by the method of Example 1, Step Cutilizing 3-(3-fluoro-4-chloro-phenyl)-acrylic acid methyl ester (34.0mmol). The crude product was purified by column chromatography (SiO₂)using a 0-45% EtOAc—hexanes gradient to afford 6.3 g (53%—two steps) ofthe subtitle compound. MS calculated for C₁₉H₁₉ClFNO₂+H: 348, observed:348.

Step C. 1-Benzyl-4-(3-fluoro-4-chloro-phenyl)-pyrrolidine-3-carboxylicacid

The subtitle compound was prepared by the method of Example 13, Step Cutilizing 1-benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acidethyl ester (18.1 mmol). The crude product was obtained without furtherpurification. MS calculated for C₁₈H₁₇ClFNO₂+H: 334, observed: 334.

Step D.2-Benzyl-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step Dutilizing 1-benzyl-4-(3-fluoro-4-chloro-phenyl)-pyrrolidine-3-carboxylicacid (18.1 mmol). The crude product was purified by columnchromatography (SiO₂) using a 0-50% EtOAc—hexanes gradient to afford thesubtitle compound. MS calculated for C₁₈H₁₅ClFNO+H: 316, observed: 316.

Step E.6-Chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 20, Step Futilizing2-benzyl-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(2.1 mmol). The crude product was obtained without further purification.MS calculated for C₁₁H₉ClFNO+H: 226, observed: 226.

Step F. N-Ethylcarbamate-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 2, Step Autilizing 6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.2 mmol). The crudeproduct was purified by column chromatography (SiO₂) using a 0-55%EtOAc—hexanes gradient to afford the subtitle compound in quantitativeyield. MS calculated for C₁₄H₁₃ClFNO₃+H: 298, observed: 298.

Step G. N-Ethylcarbamate-6-chloro-7-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 2, Step Autilizing 4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.5 mmol). The crude productwas purified by column chromatography (SiO₂) using a 10-55%EtOAc—hexanes gradient to afford 0.43 g (66%—two steps) of the subtitlecompound in quantitative yield. MS calculated for C₁₅H₁₅ClFNO₂+H: 296,observed: 296.

Step H. N-Ethylcarbamate-6-chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step Hutilizing N-ethylcarbamate-6-chloro-7-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.2 mmol). The crude product was purified by column chromatography(SiO₂) using a 0-60% EtOAc—hexanes gradient to afford the subtitlecompound in quantitative yield. MS calculated for C₁₅H₁₇ClFNO₂+H: 298,observed: 298.

Step I.6-Chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step Butilizing N-ethylcarbamate-6-chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene(0.06 mmol). An aliquot of the crude product was purified byreverse-phase liquid chromatography to afford the title compound. ¹H NMR(d₆-DMSO 300 MHz) δ 7.30 (d, 1H), 7.19 (d, 1H), 3.92 (m, 1H), 3.65 (m,1H), 3.44 (m, 2H), 3.30 (m, 2H), 2.88 (m, 1H), 1.33 (d, 3H) ppm. MScalculated for C₁₂H₁₃ClFN+H: 226, observed: 226.

Example 435-Benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

BBr₃ in CH₂Cl₂ (1.1 mL, 1.1 mmol, 1 M) was added to a solution ofN-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 2, Step A) (100 mg, 0.36 mmol) at 0° C. The reactionmixture was stirred overnight from 0° C. to room temperature andquenched with H₂O. The solution was filtered through an Extrelut column,the column was washed with CH₂Cl₂, and the filtrate was concentrated.The crude product was obtained without further purification. MScalculated for C₁₅H₁₉NO₃+H: 262, observed: 262.

Step B.N-Ethylcarbamate-5-benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Benzyl bromide (15 μL, 0.12 mmol) and K₂CO₃ (70 mg, 0.5 mmol) were addedto a solution ofN-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (26 mg, 0.1 mmol) in CH₃CN (2 mL). The resultingmixture was stirred overnight at 80° C. The reaction was cooled to roomtemperature, concentrated by rotary evaporation and taken up in H₂O (2.5mL). The product was extracted with ethyl acetate (3×5 mL). The combinedorganic extracts were dried over MgSO₄ and concentrated to afford thesubtitle compound, which was used without further purification. MScalculated for C₂₂H₂₅NO₃+H: 352, observed: 352.

Step C. 5-Benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.1 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. MS calculated forC₁₉H₂₁NO+H: 280, observed: 280.

Example 445-(2-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-(2-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

The subtitle compound was prepared by the method of Example 43, Step ButilizingN-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 43, Step A) (0.1 mmol) and 2-fluorobenzyl bromide. Thecrude product was obtained without further purification. MS calculatedfor C₂₂H₂₄FNO₃+H: 370, observed: 370.

Step B.5-(2-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step Butilizing N-ethylcarbamate-5-(2-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.1 mmol). The crude product waspurified by reverse-phase liquid chromatography to afford the titlecompound. MS calculated for C₁₉H₂₀FNO+H: 298, observed: 298.

Example 455-(3-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-(3-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

The subtitle compound was prepared by the method of Example 43, Step Butilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol)and 3-fluorobenzyl bromide. The crude product was obtained withoutfurther purification. MS calculated for C₂₂H₂₄FNO₃+H: 370, observed:370.

Step B.5-(3-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-(3-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.1 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. MS calculated forC₁₉H₂₀FNO+H: 298, observed: 298.

Example 465-(4-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-(4-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

The subtitle compound was prepared by the method of Example 43, Step ButilizingN-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 43, Step A) (0.1 mmol) and 4-fluorobenzyl bromide. Thecrude product was obtained without further purification. MS calculatedfor C₂₂H₂₄FNO₃+H: 370, observed: 370.

Step B.5-(4-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5-(4-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.1 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. MS calculated forC₁₉H₂₀FNO+H: 298, observed: 298.

Example 475-(2,6-Difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-triflate-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

Pyridine (0.9 mL, 1.08 mmol) and trifluoromethanesulfonic anhydride(0.12 mL, 0.72 mmol) were added to a solution ofN-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(from Example 43, Step A) (94 mg, 0.36 mmol) in CH₂Cl₂ (4 mL) at 0° C.The reaction solution was stirred for 2 hours from 0° C. to roomtemperature, then diluted with CH₂Cl₂. The crude product was washed withaqueous HCl (1 M), saturated aqueous NaHCO₃, and brine. The organicextracts were dried over MgSO₄ and concentrated to afford 52 mg (58%) ofthe subtitle compound. MS calculated for C₁₆H₁₈F₃NO₅S+H: 394, observed:394.

Step B.N-Ethylcarbamate-5-(2,6-difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

2,6-Difluorophenylboronic acid (41 mg, 0.26 mmol), Pd(dppf) (5 mg), andEt₃N (0.2 mL) were added to a solution ofN-ethylcarbamate-5-triflate-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(52 mg, 0.13 mmol) in DME (2.6 mL), and stirred overnight at 90° C. Thesolution was cooled to room temperature, partitioned between CH₂Cl₂ andH₂O, and filtered through an Extrelut column. The column was washed withCH₂Cl₂, and the filtrate was concentrated. The crude product wasobtained without further purification. MS calculated for C₂₁H₂₁F₂NO₂+H:358, observed: 358.

Step C.5-(2,6-Difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 2, Step ButilizingN-ethylcarbamate-5-(2,6-difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.1 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. MS calculated forC₁₈H₁₇F₂N+H: 286, observed: 286.

Example 48 5-Methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.2-Benzyl-5-methoxy-8-ethylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

Ethyltriphenylphosphonium bromide (0.6 g, 1.6 mmol) and potassiumtert-butoxide (0.18 g, 1.6 mmol) were added to a solution of2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(from Example 1, Step C) (0.32 g, 1.1 mmol) in anhydrous ether (2.2 mL).The reaction mixture was stirred for 1 hour at room temperature thenfiltered through celite. The celite was washed with ether (10 mL), andthe filtrate was concentrated. The crude product was purified by columnchromatography (SiO₂) using a 0-35% EtOAc—hexanes gradient to afford thesubtitle compound in quantitative yield. MS calculated for C₂₁H₂₃NO+H:306, observed: 306.

Step B. 5-Methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Ammonium formate (0.3 g) and palladium (10 wt. % on activated carbon,0.3 g) were added to a solution of2-benzyl-5-methoxy-8-ethylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.34 g, 1.1 mmol) in MeOH (5 mL). The reaction mixture was stirred for4 hours at 60° C. and then filtered through celite. The celite waswashed with MeOH (20 mL) and the filtrate was concentrated. The crudeproduct was purified by reverse-phase liquid chromatography to affordthe title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.05 (d, 1H), 6.75 (m,2H), 3.69 (s, 3H), 3.58 (m, 1H), 3.28 (m, 1H), 3.05 (m, 1H), 2.90 (m,3H), 2.31 (m, 1H), 2.05 (m, 1H), 1.28 (m, 1H), 1.05 (t, 3H) ppm. MScalculated for C₁₄H₁₉NO+H: 218, observed: 218.

Example 49 5-Hydroxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

Ethyl chloroformate (0.16 mL, 1.65 mmol) was added to a solution of5-methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (fromExample 48, Step B) (0.24 g, 1.1 mmol) in CH₂Cl₂ (6 mL) at 0° C. Theresulting solution was stirred overnight at room temperature. Thereaction mixture was quenched with aqueous HCl solution (20 mL, 1.0 M)and the product was extracted with EtOAc (3×10 mL). The combined organicextracts were dried over MgSO₄ and concentrated. The crude product waspurified by column chromatography (SiO₂) using a 0-35% EtOAc—hexanesgradient to afford 40 mg (13%) of the subtitle compound. MS calculatedfor C₁₇H₂₃NO₃+H: 290, observed: 290.

Step B. 5-Hydroxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 2, Step ButilizingN-ethylcarbamate-5-hydroxy-8-ethyl-12,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.07 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ6.98 (d, 1H), 6.59 (m, 2H), 3.68 (m, 1H), 3.44 (m, 1H), 3.05 (m, 4H),2.45 (m, 1H), 1.98 (m, 1H), 1.25 (m, 1H), 1.05 (t, 3H) ppm. MScalculated for C₁₃H₁₇NO+H: 204, observed: 204.

Example 505,6(2-(3-methyl)furan)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A.N-Ethylcarbamate-5-methoxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.(Scheme 1)

Icl (0.12 g, 0.72 mmol) and CaCO₃ (72 mg, 0.72 mmol) were added to asolution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.1 g, 0.36mmol) in MeOH (3.6 mL), and stirred overnight at room temperature. Thereaction mixture was filtered through celite, the celite was washed withMeOH, and the filtrate concentrated. The crude material was dissolved inEtOAc, and washed with aqueous sodium bisulfite (5% solution) and brine.The organic extracts were dried over MgSO₄ and brine. The crude productwas purified via silica plug eluting with Hexanes/EtOAc (3/1, v/v) toafford 0.14 g (97%) of the subtitle compound. MS calculated forC16H20INO₃+H: 402, observed: 402.

Step B.N-Ethylcarbamate-5-hydroxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

BBr₃ (0.7 mL, 0.7 mmol, 1 M in CH₂Cl₂) was added to a solution ofN-ethylcarbamate-5-methoxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(120 mg, 0.3 mmol) at 0° C. The reaction mixture was stirred overnightfrom 0° C. to room temperature and quenched with H₂O. The solution wasfiltered through an Extrelut column, the column was washed with CH₂Cl₂,and the filtrate was concentrated. The crude product was obtainedwithout further purification. MS calculated for Cl₅H₁₈INO₃+H: 388,observed: 388.

Step C.N-Ethylcarbamate-5-allyloxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Allyl bromide (52 μL, 0.6 mmol) and DBU (65 μL, 0.6 mmol) were added toa solution of N-ethylcarbamate-5-hydroxy-6-iodo-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (116 mg, 0.3 mmol) in CH₂Cl₂ (3 mL),and stirred 2 hours at room temperature. The reaction solution wasdiluted with H₂O and filtered through an Extrelut column. The column waswashed with CH₂Cl₂ and the filtrate was concentrated. The crude productwas purified via silica plug eluting with Hexanes/EtOAc (3/1, v/v) toafford 50 mg (39%—two steps) of the subtitle compound. MS calculated forC₁₈H₂₂INO₃+H: 428, observed: 428.

Step D.N-Ethylcarbamate-5,6(2-(3-methyl)furan)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

KOAc (40 mg, 0.36 mmol), nBu₄NBr (50 mg, 0.12 mmol), PPh₃ (3 mg, 0.1mmol), and Pd(OAc)₂ (2 mg, 6 μmol) were added to a solution ofN-ethylcarbamate-5-allyloxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(50 mg, 0.12 mmol) in DMF (1 mL), and stirred overnight at 100° C. Thereaction solution was diluted with H₂O and CH₂Cl₂, and filtered throughan Extrelut column. The column was washed with CH₂Cl₂ and the filtratewas concentrated. The crude product was obtained without furtherpurification. MS calculated for C₁₈H₂₁NO₃+H: 300, observed: 300.

Step E.5,6(2-(3-Methyl)furan)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step ButilizingN-ethylcarbamate-5,6(2-(3-methyl)furan)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole(0.1 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. MS calculated forC₁₅H₁₇₀NO+H: 228, observed: 228.

Example 515-Methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The title compound was prepared by the method of Example 1, Step Eutilizing2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(from Example 1, Step C) (2.1 mmol). The crude product was purified byreverse-phase liquid chromatography to afford the title compound. ¹H NMR(d₆-DMSO 300 MHz) δ 7.48 (d, 1H), 7.12 (d, 1H), 6.95 (dd, 1H), 3.87 (s,3H), 3.72 (m, 1H), 2.98 (m, 4H), 2.81 (m, 1H) ppm. MS calculated forC₁₂H₁₃NO₂+H: 204, observed: 204.

Example 524-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

Step A. N-Ethylcarbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one.(Scheme 1)

Ethyl chloroformate (0.18 mL, 1.9 mmol) and DIEA (1.0 mL, 5.7 mmol) wereadded to a solution of5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (fromExample 51) (0.38 g, 1.9 mmol) in CH₂Cl₂ (10 mL) at 0° C., and stirredovernight at room temperature. The reaction was quenched with aqueousHCl (1 M) and washed with brine. The organic extracts were dried overMgSO₄, and concentrated. The crude product was obtained without furtherpurification. MS calculated for C₁₅H₁₇NO₄+H: 276, observed: 276.

Step B. N-Ethylcarbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

NCS (0.25 g, 1.9 mmol) and acetic acid (10 mL) were added to a solutionof ethylcarbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(0.52 g, 1.9 mmol) in DCE (10 mL), and stirred overnight at 60° C. Thereaction was quenched with aqueous HCl (1 M) and washed with brine. Theorganic extracts were dried over MgSO₄, and concentrated. The crudeproduct was purified by column chromatography (SiO₂) using a 0-60%EtOAc—hexanes gradient to afford the subtitle compound as a mixture ofregioisomers. MS calculated for C₁₅H₁₆ClNO₄+H: 310, observed: 310.

Step C.4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 2, Step Butilizing N-ethyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.32 mmol). The crudeproduct was obtained without further purification as a mixture ofregioisomers. MS calculated for C₁₂H₁₂ClNO₂+H: 238, observed: 238.

Step D. N-tert-butylcarbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 20, Step Gutilizing4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(1.02 mmol). The crude product was purified and separated by columnchromatography (SiO₂) using a 0-60% EtOAc—hexanes gradient to afford thesubtitle compound and its regioisomer, N-tert-butylcarbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one.MS calculated for C₁₇H₂₀ClNO₄+H: 338, observed: 338.

Step E.4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The title compound was prepared by the method of Example 20, Step Iutilizing N-tert-butylcarbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(0.10 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ7.70 (d, 1H), 7.47 (d, 1H), 4.18 (m, 1H), 4.00 (s, 3H), 3.65 (m, 2H),3.58 (m, 2H), 3.45 (m, 1H) ppm. MS calculated for C₁₂H₁₂ClNO₂+H: 238,observed: 238.

Example 535-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-H-2-aza-cyclopenta[a]inden-8-one

The title compound was prepared by the method of Example 20, Step Iutilizing N-tert-butyl carbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 52, StepD) (0.10 mmol). The crude product was purified by reverse-phase liquidchromatography to afford the title compound. MS calculated forC₁₂H₁₂ClNO₂+H: 238, observed: 238.

Example 544-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

Step A. N-tert-Butylcarbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol.(Scheme 1)

NaBH₄ (4 mg, 0.1 mmol) was added to a solution of N-tert-butylcarbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one(from Example 52, Step D) (20 mg, 0.06 mmol) in MeOH (2 mL), and stirredfor 1 hour at room temperature. The reaction was partitioned between H₂Oand CH₂Cl₂, and filtered through an Extrelut column. The column waswashed with CH₂Cl₂, and the filtrate was concentrated. The crude productwas obtained without further purification as a mixture of diastereomers.MS calculated for C₁₇H₂₂ClNO₄+H: 340, observed: 340.

Step B.4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

The title compound was prepared by the method of Example 20, Step Iutilizing N-tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol (0.10 mmol). The crudeproduct was purified by reverse-phase liquid chromatography to affordthe title compound. MS calculated for C₁₂H₁₂ClNO₂+H: 240, observed: 240.

Example 555-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

Step A. N-tert-Butylcarbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

NaBH₄ (4 mg, 0.1 mmol) was added to a solution of N-tert-butylcarbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 52, StepD, regioisomer) (20 mg, 0.06 mmol) in MeOH (2 mL), and stirred for 1hour at room temperature. The reaction was partitioned between H₂O andCH₂Cl₂, and filtered through an Extrelut column. The column was washedwith CH₂Cl₂, and the filtrate was concentrated. The crude product wasobtained without further purification as a mixture of diastereomers. MScalculated for C₁₇H₂₂ClNO₄+H: 340, observed: 340.

Step B.5-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

The title compound was prepared by the method of Example 20, Step Iutilizing N-tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol (0.10 mmol). The crudeproduct was purified by reverse-phase liquid chromatography to affordthe title compound. MS calculated for C₁₂H₁₂ClNO₂+H: 240, observed: 240.

Example 56

Separation of Enantiomers for Selected Compounds of the Invention

The following compounds were separated into their respective enantiomersusing a 10 mm×250 mm Chiral Pak AD-RH chiral column. Retention FinalProducts Column Enan- Time Derived Compound Conditions tiomer (minutes)from Enantiomer Example 2, H₂O:CH₃CN 1 13.70 2, 5, 38 Step A (55:45) 219.24 1, 2, 3, 4, 5, 6, 2.6 mL/min 25, 29, 30, 31, 32, 33, 38, 43, 44,45, 46, 47, 50 Example 21, H₂O:CH₃CN 1 30.57 21 Step A (50:50) 2 32.7021 2.0 mL/min Example 23, H₂O:CH₃CN 1 17.34 15, 23 Step A (40:60) 221.49 15, 23 2.0 mL/min Example 26, H₂O:CH₃CN 1 28.47 26 Step H (40:60)2 31.17 26 2.0 mL/min Example 27, MeOH 1 10.30 27 Step D 10.0 mL/min 212.13 27 Example 34, H₂O:CH₃CN 1 23.02 34, 35 Step F (50:50) 2 26.44 34,35 1.8 mL/min Example 36, H₂O:CH₃CN 1 16.00 36 Step F (45:55) 2 23.25 361.8 mL/min Example 37, H₂O:CH₃CN 1 20.42 37 Step D (45:55) 2 28.95 371.8 mL/min Example 41, MeOH 1 9.92 41 Step H 10.0 mL/min 2 10.75 41Example 42, MeOH 1 8.05 42 Step H 10.0 mL/min 2 11.72 42

The following procedure was utilized to evaluate representativecompounds of the present invention as 5HT_(2c) receptor agonists. Theresults of this assay are set forth in Table 1.

Cell Culture

HEK 293 EBNA expressing the human 5HT2c receptor (VSV Isoform; Burns etal., NATURE 387:30308,1997) were grown in DMEM containing 10% dialysedFBS, 9 μg/ml blasticidin at 37° C. in 5% CO₂ atmosphere.

Calcium Mobilization

HEK 293 EBNA cells expressing human 5HT2_(c) receptor (2×10⁴/well) wereseeded in black 384-well collagen coated plates and incubated overnightat 37° C. in a 5% CO2/95% atmosphere. After removing medium, cells weretreated with HBSS buffer (137 mM NaCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mMHepes, pH 7.5, 2.1 mM MgCl₂, 0.3 mM CaCl₂,0.02 mM MgSO₄, 3.0 mM NaHCO₃,and 0.64 mM KH₂PO₄) containing the Calcium3 dye (Molecular Device, CA),2.5 mM probenecid and 0.08% pluronic acid for 60 minutes according tomanufacture's instruction. Compounds that were solubilized in 100% DMSOwere diluted in CsCl Ringers buffer (58.3 mM CsCl, 5.4 mM KCl, 5.5 mMGlucose, 20 mM Hepes, pH 7.5, 2.1 mM MgCl₂, 1.2 mM CaCl₂) such that thefinal DMSO concentration did not exceed 5%. 5HT was utilized as apositive control. Ligand induced calcium release and consequentfluorescence was measured on a Fluorometric Imaging Plate Reader (FLIPR,Molecular Device, CA).

Data Analysis

All data were analyzed by nonlinear least square curve fitting usingPrism 4.0 software. Agonist stimulation of calcium-induced fluorescencein FLIPR was fitted to sigmoidal dose response using equationY=Bottom+(Top−Bottom)/(1+10ˆ((LogEC50−X))), where X is the logarithm ofconcentration of compounds and Y is the fluorescent response. Example5-HT2c EC50 Number Molecule (hVSV, μM)  1 1, Enantiomer 2

>10 <1    2 2, Enantiomer 1 2, Enantiomer 2

<0.1 <1  <0.1  3 3, Enantiomer 2

<0.1 <0.1  4 4, Enantiomer 2

<1  <0.1  5 5, Enantiomer 1 5, Enantiomer 2

<0.1 <1  <1    6 6, Enantiomer 2

<1  <1    7

<10   8

<10   9

<10  10

<10  11

<0.1 <0.1 <0.1 12

>10  13

<1   14

<1   15 15, Enantiomer 1 15, Enantiomer 2

<1  <0.1 <1   16

<1   17

<10  18

<1   19

<1   20

<10  21 21, Enantiomer 1 21, Enantiomer 2

<0.1 <1  <0.1 22

<1   23 23, Enantiomer 1 23, Enantiomer 2

<1  <1  <0.1 24

<1   25, Enantiomer 2

<1   26 26, Enantiomer 1 26, Enantiomer 2

<0.1 <1  <0.1 27 27, Enantiomer 1 27, Enantiomer 2

<0.1 <1  <0.1 28

<0.1 29, Enantiomer 2

<0.1 30, Enantiomer 2

 <0.01 31, Enantiomer 2

<0.1 32, Enantiomer 2

>10  33, Enantiomer 2

<1   34, Enantiomer 1 34, Enantiomer 2

<1  <1   35, Enantiomer 1 35, Enantiomer 2

<0.1 <0.1 36, Enantiomer 1 36, Enantiomer 2

>10 <1   37, Enantiomer 1 37, Enantiomer 2

<0.1 <0.1 38 38, Enantiomer 1 38, Enantiomer 2

<0.1 <1  <0.1 39

<1   40

>10  41, Enantiomer 1 41, Enantiomer 2

<1  <10  42, Enantiomer 1 42, Enantiomer 2

<10 <0.1 43, Enantiomer 2

<10  44, Enantiomer 2

<10  45, Enantiomer 2

<10  46, Enantiomer 2

<10  47, Enantiomer 2

>10  48

>10  53

<1   54

<1   55

<10 

1. A compound of the formula

where R₁ is selected from the group consisting of H, halogen,C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, N(R₆)₂, SR₆,CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂, NR₆SO₂R₇, aryl, heteroaryl,C₁₋₁₀alkylaryl, and C₁₋₁₀alkylhetroaryl; and when m+n=1, R₁ may also beOR₆ or OCOR₇; R₂, R₃ and R₄ are independently selected from the groupconsisting of H, halogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₀alkynyl,perhaloalkyl, CN, OR₆, N(R₆)₂, SR₆, OCOR₇, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇,SO₂N(R₆)₂, NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀ alkylaryl, andC₁₋₁₀alkylhetroaryl or R₂ and R₃ together with the ring to which theyare attached form a 5 to 7 membered carbocyclic or heterocyclic ring; R₅is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, perhaloalkyl, CN, OR₆, N(R₆)₂, SR₆, OCOR₇, CON(R₆)₂,NR₆COR₇, NR₆CO₂R₇, NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀alkylaryl, and C₁₋₁₀alkylhetroaryl, or R₄ and R₅ together with the ring to which they areattached form a 6 to 8 membered aryl or heteroaryl ring; R₅a is H; or R₅and R₅a taken together form a cyclopropane ring; R₆ is selected from thegroup consisting of H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,perhaloalkyl, C₁₋₁₀ alkyl-0-C₁₋₁₀ alkyl, aryl, heteroaryl,C₁₋₁₀alkyl-O-aryl, C₁₋₁₀ alkyl-O-heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀alkylhetroaryl; and R₇ is selected from the group consisting of C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, C₁₋₁₀alkyl-O-C₁₋₁₀alkyl, aryl, heteroaryl, C₁₋₁₀alkyl-O-aryl, C₁₋₁₀alkyl-O-heteroaryl,C₁₋₁₀ alkylaryl, and C₁₋₁₀ alkylhetroaryl; provided that if R₁, R₂, R₅and R₅a are H, then R₃ and/or R₄ must be H and the pharmaceuticallyacceptable salts thereof.
 2. A compound as in claim 1 where R₁ is C₁₋₅alkyl, halogen, CF₃, aryl, heteroaryl or H; R₂, R₃ and R₄ areindependently C₁₋₅alkyl, —OR₆, halogen, CF₃, aryl, heteroaryl or H or R₂and R₃ together with the ring to which they are attached form a 5 to 7membered aryl or heteroaryl ring; R₅ is C₁₋₅-alkyl, —OR₆ or C₂₋₆alkene;and R₆ is C₁₋₅alkyl or H.
 3. A compound as in claim 1 selected from thegroup consisting of5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;5-Hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;6-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;5-(4-Flourobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;5-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole;6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;6,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;4,5-Dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;4,6-Dichloro-5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;and 6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.4. A pharmaceutical composition comprising at least one compound ofclaim 1 and a pharmaceutically acceptable carrier.
 5. A method oftreating a disease, disorder and/or condition in a patient whereinmodulation of a 5-HT_(2c) function is desired comprising administeringan effective amount of at least one compound of claim 1 to a patient inneed of such treatment.